Pharmaceutically active compounds

ABSTRACT

Compounds of general formula I:  
                 
 
     or pharmaceutically or veterinarily acceptable salts, solvates, polymorphs or pro-drugs thereof wherein:  
     wherein R 1 , R 2 , R 3 , R 4 , X and A have the meanings given herein which are useful in the curative and prophylactic treatment of a medical condition for which inhibition of a cyclic guanosine 3′,5′-monophosphate phosphodiesterase (e.g. cGMP PDE5) is desired.

FIELD OF THE INVENTION

[0001] This invention relates to pharmaceutically useful compounds, inparticular compounds which are useful in the inhibition of cyclicguanosine 3′,5′-monophosphate phosphodiesterases (cGMP PDEs), such astype 5 cyclic guanosine 3′,5′-monophosphate phosphodiesterases (cGMPPDE5). The compounds therefore have utility in a variety of therapeuticareas, including male erectile dysfunction (MED).

[0002] International patent application WO 01/27112 discloses the use ofcertain pyrazolo[4,3-d]pyrimidinone compounds in the treatment of avariety of conditions and in particular MED.

[0003] The present application provides furtherpyrazolo[4,3-d]pyrimidinone compounds.

DISCLOSURE OF THE INVENTION

[0004] According to the present invention, there are provided compoundsof general formula I:

[0005] or pharmaceutically or veterinarily acceptable salts, solvates,polymorphs or pro-drugs thereof wherein:

[0006] A represents C(O) or CH(OH);

[0007] X represents O or NR⁵;

[0008] R¹, R³, R⁴ and R⁵ independently represent H, C₁-C₆ alkyl, Het,C₁-C₆ alkylHet, aryl or C₁-C₆ alkylaryl (which latter five groups mayall be optionally substituted and/or terminated with one or moresubstituents selected from halo, cyano, nitro, OR⁶, OC(O)R⁶, C(O)R⁶,C(O)OR⁶, NR⁶C(O)NR⁷R⁸, NR⁶C(O)OR⁶, OC(O)NR⁷R⁸, C(O)NR⁹R¹⁰, NR⁹R¹⁰,SO₂NR⁹R¹⁰, SO₂R¹¹, C₁-C₆ alkyl, Het, C₁-C₆ alkylHet, aryl or C₁-C₆alkylaryl wherein said latter five substituent and/or terminal groupsare all optionally substituted and/or terminated with one or moresubstituents selected from halo, cyano, nitro, OR¹², OC(O)R¹², C(O)R¹²,C(O)OR¹², NR¹²C(O)NR¹³R¹⁴, NR¹²C(O)OR¹², OC(O)NR¹³R¹⁴, C(O)NR¹⁵R¹⁶,NR¹⁵R¹⁶, SO₂NR¹⁵R¹⁶, SO₂R¹⁷); or when X represents NR⁵ then R³ and R⁵together with the nitrogen atom to which they are bound can form aheterocyclic ring which is optionally substituted and/or terminated withone or more substituents selected from halo, cyano, nitro, OR¹²,OC(O)R¹², C(O)R¹², C(O)OR¹², NR¹²C(O)NR¹³R¹⁴, NR¹²C(O)OR¹²,OC(O)NR¹³R¹⁴, C(O)NR¹⁵R¹⁶, NR¹⁵R¹⁶, SO₂NR¹⁵R¹⁶, S₂R¹⁷;

[0009] R² represents H, halo, cyano, nitro, OR⁶, OC(O)R⁶, C(O)R⁶,C(O)OR⁶, NR⁶C(O)NR⁷R⁸, NR⁶C(O)OR⁶, C(O)NR⁷R⁸, C(O)NR⁹R¹⁰, NR⁹R¹⁰,SO₂NR⁹R¹⁰, SO₂R¹¹, C₁-C₆ alkyl, Het, C₁-C₆ alkylHet, aryl or C₁-C₆alkylaryl (which latter five groups may all be optionally substitutedand/or terminated with one or more substituents selected from halo,cyano, nitro, OR⁶, OC(O)R⁶, C(O)R⁶, C(O)OR⁶, NR⁶C(O)NR⁷R⁸, NR⁶C(O)OR⁶,OC(O)NR⁷R⁸, C(O)NR⁹R¹⁰, NR⁹R¹⁰, SO₂NR⁹R¹⁰, SO₂R¹¹, C₁-C₆ alkyl, Het,C₁-C₆ alkylHet, aryl or C₁-C₆ alkylaryl wherein said latter fivesubstituent and/or terminal groups are all optionally substituted and/orterminated with one or more substituents selected from halo, cyano,nitro, OR¹², OC(O)R¹², C(O)R¹², C(O)OR¹², NR¹²C(O)NR¹³R¹⁴, NR¹²C(O)OR¹²,OC(O)NR¹³R¹⁴, C(O)NR¹⁵R¹⁶, NR¹⁵R¹⁶, SO₂NR¹⁵R¹⁶, SO₂R¹⁷);

[0010] R⁶ represents H, C₁-C₆ alkyl, Het, C₁-C₆ alkylHet, aryl or C₁-C₆alkylaryl (which latter five groups are all optionally substitutedand/or terminated with one or more substituents selected from halo,cyano, nitro, OR¹², OC(O)R¹², C(O)R¹², C(O)OR¹², NR¹²C(O)NR¹³R¹⁴,NR¹²C(O)OR¹², OC(O)NR¹³R¹⁴, C(O)NR¹⁵R¹⁶, NR¹⁵R¹⁶, SO₂NR¹⁵R¹⁶, SO₂R¹⁷);

[0011] R⁷ and R⁸ independently represent H, C₁-C₆ alkyl, Het, C₁-C₆alkylHet, aryl or C₁-C₆ alkylaryl (which latter five groups are alloptionally substituted and/or terminated with one or more substituentsselected from halo, cyano, nitro, OR¹², OC(O)R¹², C(O)R, C(O)OR¹²,NR¹²(O)NR¹³R¹⁴, NR¹²C(O ) ¹²OC(O)N¹³R¹⁴, C(O)NR¹⁵R¹⁶, NR¹⁵R¹⁶,SO₂NR¹⁵R¹⁶, SO₂R¹⁷); or R⁷ and R⁸ together with the nitrogen atom towhich they are bound can form a heterocyclic ring;

[0012] R⁹ and R¹⁰ independently represent H, C(O)R⁶, SO₂R¹¹, C₁-C₆alkyl, Het, C₁-C₆ alkylHet, aryl or C₁-C₆ alkylaryl (which latter fivegroups are all optionally substituted and/or terminated with one or moresubstituents selected from halo, cyano, nitro, OR¹², OC(O)R¹², C(O)R¹²,C(O)OR , NR¹²C(O)NR¹³R¹⁴, NR¹²C(O)OR¹², OC(O)NR¹³R¹⁴, C(O)NR¹⁵R¹⁶,NR¹⁵R¹⁶ SO₂NR¹⁵R¹⁶, SO₂R ¹⁷); or R⁹ and R¹⁰ together with the nitrogenatom to which they are bound can form a heterocyclic ring;

[0013] wherein when R⁷ and R⁸, or R⁹ and R¹⁰ together with the nitrogenatom to which they are bound form a heterocyclic ring, said heterocyclicring is optionally substituted and/or terminated with one or moresubstituents selected from: halo, cyano, nitro, OR¹², OC(O)R¹², C(O)R¹²,C(O)OR¹², NR C(O)NR¹³R¹⁴, NR¹²C(O)OR¹², OC(O)NR¹³R¹⁴ C(O)NR¹⁵R¹⁶,NR¹⁵R¹⁶, SO₂NR¹⁵R¹⁶, SO₂R¹⁷;

[0014] R¹¹ represents a C₁-C₆ alkyl, Het, C₁-C₆ alkylHet, aryl or C₁-C₆alkylaryl group is optionally substituted and/or terminated with one ormore substituents selected from halo, cyano, nitro, OR¹², OC(O)R¹²,C(O)R¹², C(O)OR¹², NR¹²C(O)NR¹³R¹⁴, NR¹²C(O)OR¹², OC(O)NR¹³R¹⁴,C(O)NR¹⁵R¹⁶, NR¹⁵R¹⁶, SO₂NR¹⁵R¹⁶, SO₂R¹⁷;

[0015] R represents H or C₁-C₆ alkyl;

[0016] R¹³ and R¹⁴ independently represent H or C₁-C₆ alkyl; or R¹³ andR¹⁴ together with the nitrogen atom to which they are bound can form aheterocyclic ring;

[0017] R¹⁵ and R¹⁶ independently represent H, C(O)R¹², SO₂R¹⁷ or C₁-C₆alkyl; or R¹⁵ and R¹⁶ together with the nitrogen atom to which they arebound can form a heterocyclic ring;

[0018] R¹⁷ represents C₁-C₆ alkyl;

[0019] Het represents an optionally substituted four- to twelve-memberedheterocyclic group, which group contains one or more heteroatomsselected from nitrogen, oxygen, sulpur and mixtures thereof;

[0020] with the proviso that when X represents O and R¹ represents H,C₁-C₃ alkyl optionally substituted with fluoro or C₃-C₅ cycloalkyl then

[0021] R² does not represent H, C₁-C₆ alkyl optionally substituted withone or more fluoro substituents or with C₃-C₆ cycloalkyl; or

[0022] R³ does not represent C₁-C₆ alkyl optionally substituted with oneor more fluoro substituents or with C₃-C₆ cycloalkyl; C₃-C₅ cycloalkyl;C₃-C₆ alkenyl; or C₃-C₆ alkynyl; or

[0023] R₄ does not represent C₁-C₄ alkyl optionally substituted with OH,NR⁹R¹⁰, CN, CONR⁹R¹⁰, SO₂NR⁹R¹⁰ or CO₂R⁶ wherein R⁶ is H or C₁-C₄ alkyland R⁹ and R¹⁰ are each independently H or C₁-C₄ alkyl, or together withthe nitrogen atom to which they are attached form a pyrrolidinyl,piperidino, morpholino, 4-substituted piperizinyl or imidazolyl groupwherein said group is optionally substituted with C₁-C₄ alkyl or OH;C₂-C₄ alkenyl optionally substitued with CN, CONR⁹R¹⁰ or CO₂R⁶; C₂-C₄alkanoyl optionally substituted with NR⁹R¹⁰; (C₂-C₄)OH optionallysubstitued with NR⁹R¹⁰; (C₂-C₃)alkoxy(C₁-C₂)alkyl optionally substitutedwith OH or NR⁹R¹⁰.

[0024] which compounds are referred to together hereinafter as “thecompounds of the invention”.

[0025] The term “aryl”, when used herein, includes six- to ten-memberedcarbocyclic aromatic groups, such as phenyl and naphthyl.

[0026] The term “Het”, when used herein, includes four- totwelve-membered, preferably four- to ten-membered, ring systems, whichrings contain one or more heteroatoms selected from nitrogen, oxygen,sulfur and mixtures thereof, and which rings may contain one or moredouble bonds or be non-aromatic, partly aromatic or wholly aromatic incharacter. The ring systems may be monocyclic, bicyclic or fused. Theterm thus includes groups such as optionally substituted azetidinyl,pyrrolidinyl, imidazolyl, indolyl, furanyl, oxazolyl, isoxazolyl,oxadiazolyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl,oxatriazolyl, thiatriazolyl, pyridazinyl, morpholinyl, pyrimidinyl,pyrazinyl, pyridinyl, quinolinyl, isoquinolinyl, piperidinyl, pyrazolyl,imidazopyridinyl and piperazinyl. Substitution at Het may be at a carbonatom of the Het ring or, where appropriate, at one or more of theheteroatoms.

[0027] “Het” groups may also be in the form of an N-oxide.

[0028] The heterocyclic ring that R ³ and R⁵, R⁷ and R⁸, R⁹ and R¹⁰, R¹³and R¹⁴ or R¹⁵ and R¹⁶ (together with the nitrogen atom to which theyare bound) may represent may be any heterocyclic ring that contains atleast one nitrogen atom, and which ring forms a stable structure whenattached to the remainder of the molecule via the essential nitrogenatom (which, for the avoidance of doubt, is the atom to which R³ and R⁵,R⁷ and R⁸, R⁹ and R¹⁰, R¹³ and R¹⁴ or R¹⁵ and R¹⁶ are attached). In thisrespect, heterocyclic rings that R³ and R⁵, R⁷ and R⁸, R⁹ and R¹⁰, R¹³and R¹⁴ or R¹⁵ and R¹⁶ (together with the nitrogen atom to which theyare bound) may represent include four- to twelve-membered, preferablyfour- to ten-membered, ring systems, which rings contain at least onenitrogen atom and optionally contain one or more further heteroatomsselected from nitrogen, oxygen and/or sulfur, and which rings maycontain one or more double bonds or be non-aromatic, partly aromatic orwholly aromatic in character. The term thus includes groups such asazetidinyl, pyrrolidinyl, imidazolyl, indolyl, triazolyl, tetrazolyl,morpholinyl, piperidinyl, pyrazolyl and piperazinyl.

[0029] The term “C₁-C₆ alkyl” (which includes the alkyl part of alkylHetand alkylaryl groups), when used herein, includes methyl, ethyl, propyl,butyl, pentyl and hexyl groups. Unless otherwise specified, alkyl groupsmay, when there is a sufficient number of carbon atoms, be linear orbranched, be saturated or unsaturated or be cyclic, acyclic or partcyclic/acyclic. Preferred C₁-C₆ alkyl groups for use herein are C₁-C₃alkyl groups. The terms “C₂-C₆ alkenyl” and “C₂-C₆ alkynyl”, when usedherein, include C₂-C₆ groups having one or more double or triplecarbon-carbon bonds, respectively. Otherwise, the terms “C₂-C₆ alkenyl”and “C₂-C₆ alkynyl” are defined in the same way as the term “C₁-C₆alkyl”. Similarly, the term “C₁-C₆ alkylene”, when used herein, includesC₁-C₆ groups which can be bonded at two places on the group and isotherwise defined in the same way as “C₁-C₆ alkyl”. The term “acyl”includes C(O)-(C₁-C₆)alkyl.

[0030] Substituted alkylHet and alkylaryl as defined hereinbefore mayhave substituents on the ring and/or on the alkyl chain.

[0031] Halo groups with which the above-mentioned groups may besubstituted or terminated include fluoro, chloro, bromo and iodo.

[0032] Compounds of general formula (I) can be represented by formulaeIA and IB:

[0033] wherein R¹, R², R³, R⁴, A and X are as defined hereinbefore.

[0034] A preferred group of compounds according to a further aspect ofthe invention, are compounds of formulae IA or IB as hereinbeforedefined, wherein:

[0035] X represents O;

[0036] A represents C(O) or CH(OH);

[0037] R¹ represents C₁-C₆ alkyl substituted and/or terminated with OR⁶,C(O)OR⁶, C(O)NR⁹R¹⁰ or NR⁹R¹⁰ wherein said latter four groups areoptionally substituted and/or terminated as defined hereinbefore; or

[0038] R¹ represents Het, C₁-C₆ alkylHet, aryl or C₁-C₆ alkylaryloptionally substituted and/or terminated with one or more substituentsselected from halo, C₁-C₆ alkyl, OR⁶, C(O)OR⁶, C(O)NR⁹R¹⁰ and NR⁹R¹⁰wherein said latter five groups are optionally substituted and/orterminated as defined hereinbefore;

[0039] R² and R³ independently represent C₁-C₆ alkyl, Het, C₁-C₆alkylHet, aryl or C₁-C₆ alkylaryl optionally substituted and/orterminated with one or more substituents selected from halo, OR⁶,C(O)OR⁶ and NR⁹R¹⁰ wherein said latter three groups are optionallysubstituted and/or terminated as defined hereinbefore;

[0040] R⁴ represents C₁-C₆ alkyl, Het, C₁-C₆ alkylHet, aryl or C₁-C₆alkylaryl optionally substituted and/or terminated with one or moresubstituents selected from halo and OR⁶ wherein said OR⁶ group isoptionally substituted and/or terminated as defined hereinbefore;

[0041] wherein R⁶, R⁹ and R¹⁰ are as hereinbefore defined.

[0042] A highly preferred group of compounds herein are those wherein:

[0043] A represents C(O) or CH(OH);

[0044] X represents O;

[0045] R¹ represents C₁-C₆ alkyl or C₁-C₆ alkylaryl wherein both groupsare substituted and/or terminated with one or more substitutentsselected from halo, NR⁹R¹⁰, C(O)OR⁶ or C(O)NR⁹R¹⁰, or

[0046] R¹ represents Het or C₁-C₆ alkylHet wherein both groups areoptionally substituted and/or terminated with one or more substituentgroups selected from halo, OR⁶, C₁-C₆ alkyl and NR⁹R¹⁰;

[0047] R² represents C₁-C₆ alkyl optionally substituted and/orterminated with one or more substituent groups selected from halo andOR⁶; or

[0048] R² represents aryl or Het optionally substituted and/orterminated with one or more substituent groups selected from halo, OR⁶and NR⁹R¹⁰;

[0049] R³ represents C₁-C₆ alkyl, Het, C₁-C₆ alkylHet, aryl or C₁-C₆alkylaryl optionally substituted and/or terminated with one or moresubstituents selected from halo and OR⁶;

[0050] R⁴ represents C₁-C₆ alkyl optionally substituted and/orterminated with one or more substituents selected from halo and OR⁶;

[0051] wherein R⁶, R⁹ and R¹⁰ are as hereinbefore defined.

[0052] A further preferred group of compounds are those wherein:

[0053] A represents C(O) and X represents O;

[0054] R¹ represents C₁-C₆ alkyl optionally substituted and/orterminated with one or more substituent groups selected from OR , C(O)ORand C(O)NR9R¹⁰; or

[0055] R¹ represents Het or C₁-C₆ alkylHet optionally substituted and/orterminated with one or more substituent groups selected from C₁-C₆alkyl, OR⁶, C(O)OR⁶ and C(O)N R⁹R¹⁰;

[0056] R² represents C₁-C₆ alkyl optionally substituted and/orterminated with one or more substituent groups selected from halo andOR⁶;

[0057] R³ represents C₁-C₆ alkyl optionally substituted and/orterminated with one or more substituents selected from halo and OR⁶;

[0058] R⁴ represents C₁-C₆ alkyl optionally substituted and/orterminated with one or more substituents selected from halo and OR⁶;

[0059] wherein R⁶, R⁹ and R¹⁰ are as hereinbefore defined.

[0060] An additional preferred group of compounds are those wherein:

[0061] A represents C(O) and X represents O;

[0062] R¹ represents C₁-C₄ alkyl, an azetidinyl group substituted and/orterminated with one or more substituent groups selected from C₃-C₄alkyl, OR⁶, C(O)OR⁶ and C(O)NR⁹R¹⁰; or

[0063] R¹ represents a (C₁-C₆)pyridinyl group which may be optionallysubstuted with one or more substituent groups selected from C₃-C₄ alkyl,OR⁶, C(O)OR⁶ and C(O)NR⁹R¹⁰;

[0064] R² represents C₁-C₃ alkyl optionally substituted and/orterminated with one or more substituent groups selected from halo andOR⁶;

[0065] R³ represents C₁-C₄ alkyl optionally substituted and/orterminated with one or more substituents selected from halo and OR

[0066] R⁴ represents C₁-C₃ alkyl optionally substituted and/orterminated with one or more substituents selected from halo and OR⁶;

[0067] wherein R⁶ is H or a C₁-C₄ alkyl group and wherein R⁹ and R¹⁰ areindependently selected from methyl or ethyl groups.

[0068] An especially preferred group of compounds are those wherein:

[0069] A represents C(O) and X represents O;

[0070] R¹ represents C₂-C₃ alkyl group substituted and/or terminatedwith one or more substituent groups selected from OR⁶ or C(O)OR⁶;

[0071] R² represents C₂-C₃ alkyl, and is preferably ethyl, optionallysubstituted and/or terminated with one or more substituent groupsselected from halo and OR⁶;

[0072] R³ represents C₃-C₄ alkyl, and is preferably propyl, optionallysubstituted and/or terminated with one or more substituents selectedfrom halo and OR⁶;

[0073] R⁴ represents C₁-C₂ alkyl, and is preferably ethyl, optionallysubstituted and/or terminated with one or more substituents selectedfrom halo and OR⁶;

[0074] wherein R⁶ is H or a C₂-C₄ alkyl group.

[0075] Especially preferred herein are compounds of formula I asdescribed in the Examples section herein and in particular:

[0076]5-(5-Acetyl-2-butoxyphenyl)-2-(1-cyclobutyl-3-azetidinyl)-3-ethyl-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one;

[0077]tert-Butyl-5-[(5-acetyl-2-propoxyphenyl)-3-ethyl-7-oxo-6,7-dihydro-1H-pyrazolo[4,3-d]pyrimidin-1-yl]-acetate;

[0078]tert-Butyl-5-[(5-acetyl-2-propoxyphenyl)-3-ethyl-7-oxo-6,7-dihydro-2H-pyrazolo[4,3-d]pyrimidin-2-yl]-acetate;

[0079]tert-Butyl-3-[(5-acetyl-2-propoxyphenyl)-3-ethyl-7-oxo-6,7-dihydro-1H-pyrazolo[4,3-d]pyrimidin-1-yl]-2-methylpropanoate;

[0080]Ethyl-2-[5-(5-acetyl-2-propoxyphenyl)-3-ethyl-7-oxo-6,7-dihydro-2H-pyrazolo[4,3-d]pyrimidin-2-yl]propanoate;

[0081]Methyl-4-[5-(5-acetyl-2-propoxyphenyl)-3-ethyl-7-oxo-6,7-dihydro-1H-pyrazolo[4,3-d]pyrimidin-1-yl]-butanoate;

[0082]Methyl-4-[5-(5-acetyl-2-propoxyphenyl)-3-ethyl-7-oxo-6,7-dihydro-2H-pyrazolo[4,3-d]pyrimidin-1-yl]-butanoate;

[0083]4-[5-(5-Acetyl-2-propoxyphenyl)-3-ethyl-7-oxo-6,7-dihydro-1H-pyrazolo[4,3-dpyrimidin-1-yl]butanoic acid;

[0084]4-[5-(5-Acetyl-2-propoxyphenyl)-3-ethyl-7-oxo-6,7-dihydro-2H-pyrazolo[4,3-d]pyrimidin-2-yl]butanoicacid;

[0085]2-[5-(5-Acetyl-2-propoxyphenyl)-3-ethyl-7-oxo-6,7-dihydro-2H-pyrazolo[4,3-d]pyrimidin-2-yl]-N,N-dimethylacetamide

[0086] and pharmaceutically acceptable salts, solvates and polymorphsthereof.

[0087] The present invention additionally provides compounds of generalformula I:

[0088] or pharmaceutically or veterinarily acceptable salts, solvates,polymorphs or pro-drugs thereof wherein:

[0089] A represents C(O) or CH(OH);

[0090] X represents O or NR⁵;

[0091] R¹, R³, R⁴ and R⁵ independently represent H, C₁-C₆ alkyl, Het,C₁-C₆ alkylHet, aryl or C₁-C₆ alkylaryl (which latter five groups mayall be optionally substituted and/or terminated with one or moresubstituents selected from halo, cyano, nitro, OR⁶, OC(O)R⁶, C(O)R,C(O)OR⁶, NR⁶C(O)NR⁷R⁸, NR⁶C(O)OR⁶, OC(O)NR⁷R⁸, C(O)NR⁹R¹⁰, NR⁹R¹⁰,SO₂NR⁹R¹⁰, SO₂R¹⁰, C₁-C₆ alkyl, Het, C₁-C₆ alkylHet, aryl or C₁-C₆alkylaryl wherein said latter five substituent and/or terminal groupsare all optionally substituted and/or terminated with one or moresubstituents selected from halo, cyano, nitro, OR¹², OC(O)R¹², C(O)R¹²,C(O)OR¹², NR¹²C(O)NR¹³R¹⁴, NR¹²C(O)OR¹², OC(O)NR¹³R¹⁴, C(O)NR¹⁵R¹⁶,NR¹⁵R¹⁶, SO₂NR¹⁵R¹⁶, SO₂R¹⁷); or R³ and R⁵ together with the nitrogenatom to which they are bound can form a heterocyclic ring which isoptionally substituted and/or terminated with one or more substituentsselected from halo, cyano, nitro, OR¹², OC(O)R¹², C(O)R¹², C(O)OR¹²,NR¹²C(O)NR¹³R¹⁴, NR¹²C(O)OR¹², OC(O)NR¹³R¹⁴, C(O)NR¹⁵R¹⁶, NR¹⁵R¹⁶,SO₂NR¹⁵R¹⁶, SO₂R¹⁷;

[0092] R² represents H, halo, cyano, nitro, OR⁶, OC(O)R⁶, C(O)R⁶,C(O)OR⁶, NR⁶C(O)NR⁷R⁸, NR⁶C(O)OR⁶, OC(O)NR⁷R⁸, C(O)NR⁹R¹⁰, NR⁹R¹⁰,SO₂NR⁹ R¹, SO₂R¹¹, C₁-C₆ alkyl, Het, C₁-C₆ alkylHet, aryl or C₁-C₆alkylaryl (which latter five groups may all be optionally substitutedand/or terminated with one or more substituents selected from halo,cyano, nitro, OR⁶, OC(O)R⁶, C(O)R⁶, C(O)OR⁶, NR⁶C(O)NR⁷R⁸, NR⁶C(O)OR⁶,OC(O)NR⁷R⁸, C(O)NR⁹R¹⁰, NR⁹R¹⁰, SO₂NR⁹R¹⁰, SO₂R¹¹, C₁-C₆ alkyl, Het,C₁-C₆ alkylHet, aryl or C₁-C₆ alkylaryl wherein said latter fivesubstituent and/or terminal groups are all optionally substituted and/orterminated with one or more substituents selected from halo, cyano,nitro, OR¹², OC(O)R¹², C(O)R¹², C(O)OR¹², NR¹²C(O)NR¹³R¹⁴, NR¹²C(O)OR¹²,OC(O)NR¹³R¹⁴, C(O)NR¹⁵R¹⁶, NR¹⁵R¹⁶, SO₂NR¹⁵R¹⁶, SO₂R¹⁷);

[0093] R⁶ represents H, C₁-C₆ alkyl, Het, C₁-C₆ alkylHet, aryl or C₁-C₆alkylaryl (which latter five groups are all optionally substitutedand/or terminated with one or more substituents selected from halo,cyano, nitro, OR¹², OC(O)R¹², C(O)R¹², C(O)OR¹², NR¹²C(O)NR¹³R¹⁴,NR¹²C(O)OR¹², OC(O)NR¹³R¹⁴, C(O)NR¹⁵R¹⁶, NR¹⁵R¹⁶, SO₂NR¹⁵R¹⁶, SO₂R¹⁷);

[0094] R⁷ and R⁸ independently represent H, C₁-C₆ alkyl, Het, C₁-C₆alkylHet, aryl or C₁-C₆ alkylaryl (which latter five groups are alloptionally substituted and/or terminated with one or more substituentsselected from halo, cyano, nitro, OR¹² OC(O)R¹², C(O)R¹², C(O)OR¹²,NR¹²(O)NR¹³R¹⁴, NR¹²C(O)OR¹², OC(O)NR¹³R¹⁴, C(O)NR¹⁵R¹⁶, NR¹⁵R¹⁶,SO₂NR¹⁵R¹⁶, SO₂R¹⁷); or R⁷ and R⁸ together with the nitrogen atom towhich they are bound can form a heterocyclic ring;

[0095] R⁹ and R¹⁰ independently represent H, C(O)R⁶, SO₂R¹¹, C₁-₆ alkyl,Het, C₁-C₆ alkylHet, aryl or C₁-C₆ alkylaryl (which latter five groupsare all optionally substituted and/or terminated with one or moresubstituents selected from halo, cyano, nitro, OR¹², OC(O)R¹², N(O)R¹²,C(O)OR¹², NR¹²C(O)NR¹³R¹⁴, NR¹²(O)OR¹², OC(O)NR¹³R¹⁴, C(O)NR¹⁵R¹⁶,NR¹⁵R¹⁶, SO₂NR¹⁵R¹⁶, SO₂R¹⁷); or R⁹ and R¹⁰ together with the nitrogenatom to which they are bound can form a heterocyclic ring;

[0096] R¹¹ represents a C₁-C₆ alkyl, Het, C₁-C₆ alkylHet, aryl or C₁-C₆alkylaryl group is optionally substituted and/or terminated with one ormore substituents selected from halo, cyano, nitro, OR¹², OC(O)R¹²,C(O)R¹², C(O)OR¹², NR¹²C(O)NR¹³R¹⁴, NR¹²C(O)OR¹², OC(O)NR¹³R¹⁴,C(O)NR¹⁵R¹⁶, NR¹⁵R¹⁶, SO₂NR¹⁵R¹⁶, SO₂R¹⁷;

[0097] R¹² represents H or C₁-C₆ alkyl;

[0098] R¹³ and R¹⁴ independently represent H or C₁-C₆ alkyl; or R¹³ andR¹⁴ together with the nitrogen atom to which they are bound can form aheterocyclic ring;

[0099] R¹⁵ and R¹⁶ independently represent H, C(O)R¹², SO₂R¹⁷ or C₁-C₆alkyl; or R¹⁵ and R¹⁶ together with the nitrogen atom to which they arebound can form a heterocyclic ring;

[0100] wherein when R⁷ and R⁸, or R⁹ and R¹⁰ together with the nitrogenatom to which they are bound form a heterocyclic ring, said heterocyclicring is optionally substituted and/or terminated with one or moresubstituents selected from: halo, cyano, nitro, OR¹², OC(O)R¹², C(O)R¹²C(O)OR¹², NR¹²C(O)NR¹³R¹⁴, NR¹²(O)OR¹², OC(O)NR¹³R¹⁴, C(O)NR¹⁵R¹⁶,NR¹⁵R¹⁶ SO₂NR¹⁵R¹⁶, SO₂ ¹⁷;

[0101] R¹⁷ represents C₁-C₆ alkyl;

[0102] Het represents an optionally substituted four- to twelve-memberedheterocyclic group, which group contains one or more heteroatomsselected from nitrogen, oxygen, sulpfur and mixtures thereof;

[0103] with the proviso that when X represents O then R¹ does notrepresent H, unsubstituted C₁-C₆ alkyl or C₁-C₆ alkyl substituted and/orterminated by one or more halo substituents.

[0104] The compounds of formula 1, and their pharmaceutically acceptablesalts, have the advantage that they are inhibitors of the cGMP PDE5enzyme, they have desirable potency, they demonstate desirableselectivity or have other more desirable properties versus the compoundsof the prior art

[0105] For successful utility within the pharmaceutical industry it isdesirable that an active material should have good physical chemicalproperties, such as for example solubility. In some cases compounds canexhibit desirable medicinal properties which cannot be translateddirectly into a suitable pharmaceutical composition because the activecompound itself has unsatisfactory physical properties such as forexample poor chemical or processing properties.

[0106] The highly preferred compounds herein demonstrate desirablesolubility characteristics in conjunction with desirable pharmacologicalproperties, potency and selectivity.

[0107] Compounds of general formulae (I), (IA) or (IB) are referred toherein after as “the compounds of the invention” or “the compounds”.

[0108] The pharmaceutically or veterinarily acceptable salts of thecompounds which contain a basic centre are, for example, non-toxic acidaddition salts formed with inorganic acids such as hydrochloric,hydrobromic, hydroiodic, sulphuric and phosphoric acid, with carboxylicacids or with organo-sulphonic acids. Examples include the HCl, HBr, Hi,sulphate or bisulphate, nitrate, phosphate or hydrogen phosphate,acetate, benzoate, succinate, saccarate, fumarate, maleate, lactate,citrate, tartrate, gluconate, camsylate, methanesulphonate,ethanesulphonate, benzenesulphonate, p-toluenesulphonate and pamoatesalts. Compounds of the invention can also provide pharmaceutically orveterinarily acceptable metal salts, in particular non-toxic alkali andalkaline earth metal salts, with bases. Examples include the sodium,potassium, aluminium, calcium, magnesium, zinc and diethanolamine salts.For a review on suitable pharmaceutical salts see Berge et al, J. Pharm,Sci., 66, 1-19, 1977.

[0109] The pharmaceutically acceptable solvates of the compounds includethe hydrates thereof.

[0110] Also included within the scope herein are various salts of thecompounds and polymorphs thereof.

[0111] Where a compound contains one or more asymmetric carbon atoms ittherefore exists in two or more stereoisomeric forms. Where a compoundcontains an alkenyl or alkenylene group, cis (E) and trans (Z) isomerismmay also occur. The present invention includes the individualstereoisomers of the compound and, where appropriate, the individualtautomeric forms thereof, together with mixtures thereof. Separation ofdiastereoisomers or cis and trans isomers may be achieved byconventional techniques, e.g. by fractional crystallisation,chromatography or H.P.L.C. of a stereoisomeric mixture of a compound ofthe formula (I) or a suitable salt or derivative thereof. An individualenantiomer of a compound may also be prepared from a correspondingoptically pure intermediate or by resolution, such as by H.P.L.C. of thecorresponding racemate using a suitable chiral support or by fractionalcrystallisation of the diastereoisomeric salts formed by reaction of thecorresponding racemate with a suitable optically active acid or base, asappropriate. All stereoisomers of the compounds are included within thescope herein.

[0112] The compounds may exhibit tautomerism. All tautomeric forms ofthe compounds, and mixtures thereof, are included within the scopeherein.

[0113] Also included within the scope of the application areradiolabelled derivatives of the compounds which are suitable forbiological studies.

[0114] Preparation

[0115] The compounds may be prepared in accordance with the methodsdetailed in the example and preparations section herein after. Morespecifically, routes by which the compounds herein may be prepared areas illustrated in Schemes 1, 2, 3 and 4 below:

[0116] In the compounds of Scheme 1 R¹, R², R³, R⁴, A and X are ashereinbefore defined, P is either H or a protecting group, such as forexample a methyl, ethyl or n-butyl group and Hal is a halogen,preferably Br or I. When P is an ester protecting group such group maybe readily converted to the corresponding acid via suitable hydrolysis.

[0117] The compounds of Scheme 1 wherein A═CH(OH) can be prepared fromthe compounds of Scheme I wherein A═C(O) at any suitable stage in theroute illustrated. Such transformation may be effected via use of asuitable reducing agent, preferably sodium borohydride in methanol. Thereverse transformation can be effected via use of suitable oxidisingconditions, such as for example magnesium dioxide oxidation.

[0118] The cyclodehydration reaction of Step A may be accomplished underbasic, neutral or acidic conditions using known methods for pyrimidonering formation. Preferably, the cyclisation is performed under eitherbasic conditions such as by using an alkali metal salt of an alcohol oramine, such as sodium ethoxide, potassium tert-butoxide, cesiumcarbonate or potassium bis(trimethylsilyl)amide, in the presence of asuitable alcoholic solvent, such as ethanol, for example at refluxtemperature and optionally elevated pressure (or, if performed in asealed vessel, at greater than reflux temperature), or the cyclisationcan be performed under acidic conditions using polyphosphoric acid. Theskilled person will appreciate that, when X represents O and an alcoholis selected as solvent, an appropriate alcohol of formula R³OH, may beused if it is intended to mitigate alkoxide exchange at the 2-positionof the phenyl.

[0119] In general, Step A can be base mediated by using an alkali metalsalt such as for example Cs₂CO₃, K₂CO₃, potassiumbis(trimethylsilyl)amide (KHMDS) or KO^(t)Bu, in an alcoholic solvent,preferably of formula R³OH, or using a sterically hindered alcohol assolvent (e.g. 3-methyl-3-pentanol) at between about 70° C. to the refluxtemperature of the selected solvent, for from 6 to about 30 hours,optionally at elevated pressure and optionally in the presence of ahydroxide scavenger, preferably R³OAc.

[0120] Similarly, Step A can be acid mediated such as by treatment witheither polyphosphoric acid at from about 130 to about 150° C. or with aLewis acid, e.g. anhydrous zinc chloride at from about 200 to about 220°C.

[0121] Preferably Step A is carried out with from about 2 to 3equivalents of Cs₂CO₃ or KOBu^(t) in R³OH, optionally in the presence ofabout 1 to 2 equivalents of R³OAc, at the reflux temperature of thesolvent, and optionally at elevated pressure, for between about 6 hoursand about 5 days.

[0122] When X—R³ is —OR³ in the compound obtained from Step A, then itis possible to start Step A from a compound having either an —OR³ or an—OR^(3a) group wherein —OR^(3a) represents —OR³ or any alternativealkoxy group which is replaceable by —OR³. Suitable OR^(3a) groupsinclude methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy and any otheralkoxy group capable of being exchanged for —OR³ wherein R³ is asdefined hereinbefore. As defined herein OR^(3a), for example when —OR³is ethoxy may either be ethoxy or be any alternative alkoxy group whichis replaceable by ethoxy.

[0123] The coupling reaction of Step B may be achieved by conventionalamide bond forming techniques which are well known to those skilled inthe art. For example, an acyl halide (e.g. chloride) derivative of thestarting benzoic acid with the pyrazole compound in the presence of anexcess of a tertiary amine, such as triethylamine or pyridine,optionally in the presence of a suitable catalyst, such as4-dimethylaminopyridine, in a suitable solvent such as dichloromethaneor THF, at a temperature of about 0° C. to room temperature.

[0124] A variety of other amino acid coupling methodologies may be usedto couple the benzoic acid compounds to the pyrazole compoundsillustrated in Scheme 1. For example, the acid or a suitable saltthereof (e.g. sodium salt) may be activated with an appropriateactivating reagent, e.g. a carbodiimide, such as1,3-dicyclohexylcarbodiimide or1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride optionallyin the presence of 1-hydroxybenzotriazole hydrate and/or a catalyst suchas 4-dimethylaminopyridine; a halotrisaminophosphonium salt such asbromo-tris(pyrrolidinyl)phosphonium hexafluorophosphate; a suitablepyridinium salt such as 2-chloro-1-methyl pyridinium chloride; oranother suitable coupling agent such asO-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyl-uroniumhexafluorophosphate (HATU). Either type of coupling reaction may beconducted in a suitable solvent such as dichloromethane, tetrahydrofuranor N,N-dimethylformamide, optionally in the presence of a tertiary aminesuch as N-methylmorpholine or N-ethyldiisopropylamine (for example wheneither the pyrazole compound, or the activating agent is presented inthe form of an acid addition salt), at from about 0° C. to about roomtemperature. Preferably, from about 1 to 2 molecular equivalents of theactivating reagent and from 1 to 3 molecular equivalents of any tertiaryamine present may be employed.

[0125] Alternatively, the carboxylic acid function of the benzoic acidcompound may be activated using an excess of a suitable acid acceptorreagent such as N,N′-carbonyldiimidazole in an appropriate solvent, e.g.ethyl acetate, dichloromethane or butan-2-one, at from about roomtemperature to about 80° C., followed by reaction of the intermediateimidazolide with a pyrazole compound at from about 20° C. to about 90°C.

[0126] In a further variation, the final cyclised compound (of generalformula (I), (IA) or (IB), as defined previously herein and asillustrated in the general process of Scheme 1), may be formed in aone-pot procedure by coupling the pyrazole compound and the acylchloride derivative of the benzoic acid illustrated in Scheme 1 and bycyclising the resultant intermediate compound using the methods asdescribed previously. The one-pot procedure may further involve anin-situ coupling and cyclisation reaction to form a compound of formula(I), (IA) or (IB). Preferably, pyridine may serve as an acid scavengerand as the solvent for the in-situ coupling and cyclisation reaction.

[0127] Typical conditions for Step B require the acid chloride (of thebenzoic acid compound), the pyrazole compound and trimethylamine orpyridine at from 0° C. to about room temperature for up to about 16hours. Alternative conditions for Step B require the acid, the pyrazolocompound, O-(7-azabenzotriazol-1-yl)-N,N,N′N′-tetramethyluroniumhexafluor-phosphate (HATU reagent)/(PyBOP®)Benzotriazol-1-yloxytris(pyrrolidino) phosphoniumhexafluorophosphate/(PYBrOP) bromo-tris-pyrrolidino-phosphoniumhexafluorophosphate/Mukaiyama's reagent (2-chloro-1-methylpyridiniumiodide) or 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride(WSCDI)/N,N′-dicyclohexylcarbodiimide (DCC) and(HOBT)/1-hydroxy-7-azabenzotriazole (HOAT), with an excess of N-methylmorpholine (NMM), or triethylamine, or Hunigs base in THF,dichloromethane or ethyl acetate, at room temperature for from about 1to about 48 hrs.

[0128] Preferred conditions for Step B are using about 1 equivalent ofthe acid chloride and about 1 equivalent of the pyrazole with an excess(about 3 equivalents) of triethylamine in dichloromethane for about 3hours at room temperature.

[0129] Step C is an alkylation reaction with R¹L, where L is a suitableleaving group, such as halo, tosylate, mesylate, in the presence of abase, optionally in the presence of a catalyst, in a solvent at between0° C. and the reflux temperature of the solvent. Typical conditionsutilise a slight excess of R¹L, a slight excess of base, such as K₂CO₃or Cs₂CO₃, in DMF or MeCN, at between about 40° C. and about 100° C.

[0130] Preferred conditions for Step C use from about 1.2 to about 2equivalents of R¹L, (wherein L is preferably Cl, I or mesylate ortosylate), and from about 1.2 to about 1.5 equivalents of Cs₂CO₃, in DMFat between about 50° C. and about 90° C. for from about 16 to about 34hours.

[0131] In Step C the R¹ group may be a protected group as illustratedbelow:

[0132] Step D provides functionalisation at a position alpha to theketone substituent (at the 5′ position on the phenyl ring). Suchfunctionalisation of for example a methyl ketone to a substituted methylketone can occur at any step and in any route. Step D applies when Arepresents C═O and R⁴ represents methylene substituted with groupsdefined hereinbefore. Using standard conditions to enable halogenation,preferably bromination, alpha- to the ketone to form alpha-halo ketones,or conditions to enable oxidation alpha- to the ketone where theresulting alpha-hydroxy group is converted to a leaving group. Thehalogen or oxygenated leaving group can then be displaced by a suitablenucleophile, e.g. primary or secondary amine.

[0133] Preferred conditions for step D are bromination using about 1.1equivalent of N-bromosuccinimide, about 3 equivalents of triflic acidand dichloromethane. Alternatively, addition of a base will allowformation of the enolate, which can then be quenched on to a suitableelectrophile (e.g. lower alkyl halide). Typical conditions for suchtransformation are form about 1.1 to about 2 equivalents of suitablebase (e.g. LDA, NaH), from about 1.1 to about 2 equivalents of suitableelectrophile (e.g. lower alkyl halides) in THF or ether followed byreaction with an R⁴L group wherein L is a suitable leaving group.Advantageously, during Step D ester hydrolysis can also occur therebyenabling acid coupling with the pyrazole amine following isolation ofthe acidic product.

[0134] These transformations can occur when P=H or protecting group (asdetailed hereinbefore).

[0135] Step E introduces a functionalised ketone moiety into the phenylcompound. Conversion of Hal to A—R⁴ can occur at any step in any of theroutes. This can be achieved by any one of the routes outlined below:

[0136] (a) so-called “Heck” conditions (e.g. 2 eq. of a source of anacyl anion equivalent (such as butyl vinyl ether), 1.7 eq. of Et₃N andcatalytic amounts of Pd(OAc)₂ and P(o-tol)₃, in MeCN at between roomtemperature and reflux). Performing a Heck reaction on an alkyl alkenylether (will give products where A represents C═O). Such reactions arenot suitable when R⁴ is aryl; or

[0137] (b) so-called “Sonogashira” conditions (for example as describedin Synthesis 1980, 8, 627, such as 1.5 to 5 eq. of a terminal alkyne and0.024 to 0.03 eq. of Pd(PPh₃)₂Cl₂/Cul, in Et₃N and MeCN at between roomtemperature and 60° C.), followed by hydrolysis of the resultant alkyne(typical conditions 0.3 equiv. HgSO₄, H₂SO₄, acetone at reflux). Note,this procedure will give products where A represents C═O. Such reactionsare not suitable when R⁴ is aryl; or

[0138] (c) Halogen/lithium exchange followed by quenching onto an acylchloride (to give products where A represents C═O). Alternatively, theanion could be quenched onto an aldehyde to give products where Arepresents CH(OH). This alcohol could then be re-oxidised to thecorresponding ketone by methods described hereinbefore. Preferredconditions for acyl chloride reaction: 1-2 equivalents of n-ButylLithium, 1-2 equivalents of R⁴COCl, THF, at from about −78° C. to aboutroom temperature. If for example R⁴COCl is LCH₂COCl (where L is aleaving group as defined earlier), then once the above procedure hasbeen performed the product can be further functionalised by displacementof L with a nucleophile (e.g. primary or secondary amine)

[0139] (d) Formation of Grignard or zincate through addition ofmagnesium or a zinc source (e.g. zinc, zinc chloride, Reike zinc),followed by quenching onto an acyl chloride (to give products where Arepresents C═O). Alternatively the Grignard or zinc reagent could bequenched onto an aldehyde to give products where A represents CH(OH).Again, the alcohol formed could be oxidised to give the required ketoneas detailed hereinbefore.

[0140] (e) Carbonylation to yield a carboxylic acid, ester, or Weinrebamide. Preferred conditions: CO (50 psi), Pd(OAc)₂ (0.03 eq.),1,1′-bis(diphenylphosphino)ferrocene (0.045 eq.), triethylamine (5 eq.),and suitable nucleophile (e.g. alcohol, amine) at from 40 to about 80°C. Alternatively the Weinreb amide can be synthesised from thecarboxylic acid and the aldehyde could be synthesised from the ester orcarboxylic acid. The acid chloride can be formed from the carboxylicacid. Preferred conditions to from acid chloride from acid: (COCl)₂ (1.2eq.), DMF (drop), DCM. A nucleophile such as a Grignard reagent orzincate can then be reacted with the ester, Weinreb amide or acidchloride to yield products where A represents C═O. Alternatively,analogous reactions with the aldehyde would yield products where Arepresents CH(OH). Preferred conditions for addition of Grignard reagentinto acid chloride: R⁴ MgBr (1 eq.), Fe(acac)₃ (0.03 eq.), THF.

[0141] Advantageously, during Step E “in-situ” hydrolysis of the esterprotecting group can occur thereby enabling acid coupling with thepyrazole amine following isolation of the acidic product.

[0142] These transformations can occur when P═H or protecting group (asdetailed hereinbefore).

[0143] Step F illustrates the formation of a methyl ketone from theappropriate halogenated phenyl compound. Conversion of Hal to C(O)Me canoccur at any step in any of the routes, by the methods outlined in E(a)to (e) above.

[0144] Step G illustrates the halogenation of 2-alkoxy benzoates whereinHal represents Cl, Br or I, preferably Br or I. Typical conditions forhalogenation are N-iodosuccinimide (1 to 2 eq.), trifluoroaceticacid:trifluoroacetic anhydride (4:1 mixture as solvent) at temperaturesbetween room temperature and reflux. Once halogenation has occurred the2-alkoxy substituent can be exchanged with alternative alkoxy or aminosubstituents. This 2′ exchange reaction can also occur at any subsequentstep in the synthesis of the compounds of general formula (I). Typicalconditions for 2′ exchange with alternative alkoxy substituents areCs₂CO₃ (2 to 4 eq.) or KO^(t)Bu (1 to 3 eq.) or KHMDS (2 to 5 eq.), ROHas solvent at temperatures between room temperature and reflux. Typicalconditions for 2′ exchange with amino substituents are copper sulphate(catalytic), R′R″NH₂ at temperatures between room temperature andreflux.

[0145] Step H provides for acylation at the C-5 position of the phenylring using Friedel Crafts reactions (to give products where A representsC═O). Typical conditions: AlCl₃ (2 to 10 eq.), RCOCl (1 to 3 eq.), DCMat 0° C. to reflux.

[0146] An alternative synthesis of the starting acid in reaction B(compound P), where A-R⁴ is acetyl can be accomplished in two steps(reactions O and N) from a protected acid (compound Q) as illustratedbelow:

[0147] In Step N the protected acid R undergoes ester hydrolysis understandard conditions, typically using about 2 equivalents of sodiumhydroxide in a dioxan:water mixture with a volume ratio of 10:1 at roomtemperature for about 18 hours.

[0148] In Step O the alkylation reaction (of the OH group) is typicallyaccomplished by use of from about 4.5 to about 6 equivalents of R³Lwherein L is a suitable leaving group, and wherein L is preferably 1,with about 3 to about 4.5 equivalents of a suitable base, such as K₂CO₃in an appropriate solvent such as acetonitrile for 3 to 4 days at 60° C.to about 80° C.

[0149] Scheme 2 illustrates the preparation of the compounds via aprocess wherein the R¹ substituent is included as the final step.

[0150] In Scheme 2, A, X, R¹, R², R³ and R⁴ are as hereinbefore defined.Step C is an alkylation reaction with R¹L, where L is a suitable leavinggroup, such as halo, tosylate, mesylate, in the presence of a base,optionally in the presence of a catalyst, in a solvent at between 0 and40° C. Typical conditions utilise an excess of R¹L, a slight excess ofbase, such as K₂CO₃ or Cs₂CO₃, in DMF or MeCN, at between about 0 andabout 40° C.

[0151] Preferred conditions for step C use from about 1.0 to about 1.1equivalents of R¹L, (wherein L is preferably Cl), and about 1.4 to about1.6, more preferably about 1.5 equivalents of Cs₂CO₃, in DMF at roomtemperature from 24 to about 72 hours.

[0152] Steps A and B can be carried out using the conditions andreagents as detailed herein before in relation to Scheme 1.

[0153] Illustrated in Scheme 3 is a general process whereby, when R² maybe added to the general structure.

[0154] In Scheme 3, A, X, R¹, R², R³ and R⁴ are as hereinbefore definedand Hal is Cl, Br or I.

[0155] Step I provides for halogenation at the C-3 position on thepyrazole ring. In Step I, Hal represents Cl, Br or I in this instanceand is preferably Br. Typical conditions for bromination are bromine(1.5 to 2 equiv.) and sodium acetate (1.5 to 2 equiv.) in a suitablesolvent (e.g. acetic acid) at temperatures between room temperature andthe reflux temperature of the solvent. Optionally, this halogenationstep can be performed at other stages in the reactions sequenceillustrated in Scheme 3 (i.e. before cyclisation or before coupling).

[0156] In Step J, wherein Hal=I, Pd coupling is used to introduce the R²group. Such reagents are applicable where R² is alkyl, alkylHet, Het,Aryl or alkylAryl (all optionally substituted as defined hereinbefore),as well as cyano, C(O)R⁶ and C(O)O R⁶ (wherein R⁶ is as describedhereinbefore) using coupling conditions such as are known to thoseskilled in the art.

[0157] (a) so-called “Suzuki” conditions (e.g. 1.2 eq. of boronic acid,2 eq. of K₂CO₃ and 0.1 eq. of Pd(PPh₃)₄, refluxing in an approximately4:1 mixture of dioxane:water, or 2.5 to 3 eq. of CsF, 0.05 to 0.1 eq. ofPd₂(dba)₃ and 0.01 to 0.04 eq of P(o-tol)₃, refluxing in DME);

[0158] (b) so-called “Stille” conditions (e.g. 1.5 eq. of stannane, 10eq. of LiCl, 0.15 eq. of Cul, and 0.1 eq. of Pd(PPh₃)₄, refluxing indioxane, or 5 eq. of stannane, 3.6 eq. of Et₃N, Pd₂(dba) and P(o-tol)₃,refluxing in MeCN);

[0159] (c) so-called “Heck” conditions (e.g. 2 eq. of a source of anacyl anion equivalent (such as butyl vinyl ether), 1.7 eq. of Et₃N andcatalytic amounts of Pd(OAc)₂ and P(o-tol)₃, in MeCN at between roomtemperature and reflux); or

[0160] (d) so-called “Sonogashira” conditions (for example as describedin Synthesis 1980, 8, 627, such as 1.5 to 5 eq. of a terminal alkyne and0.024 to 0.03 eq. of Pd(PPh₃)₂Cl₂/Cul, in Et₃N and MeCN at between roomtemperature and 60° C.); or

[0161] (e) carbonylation conditions such as reaction with an appropriatepalladium catalyst system (e.g. palladium(II) acetate combined with1,2-bis(diphenylphosphino)-propane (DPPP)) under an atmosphere of carbonmonoxide (e.g. at a pressure of around 482.6 kPa (70 psi)) in thepresence of an excess of an alcohol, an excess of a tertiary amine base(e.g. Et₃N), and optionally in the presence of a suitable solvent (e.g.dimethylsulfoxide).

[0162] The skilled chemist would appreciate that the steps describedabove can be carried out in any order, for example the conversion of Halto —AR⁴, optionally via C(O)Me, can take place either before or aftercoupling or before or after cyclisation.

[0163] Steps A and B are as hereinbefore detailed.

[0164] Scheme 4 illustrates a general process wherein compounds offormula (I) can be prepared from similar compounds wherein R¹ isintroduced onto a protected pyrimidinone.

[0165] In Scheme 4, A, X, R¹, R², R³ and R⁴ are as hereinbefore defined.

[0166] Step K involves the removal of pyrimidinone protecting groupwherein P is a hydroxy protecting group, preferably Me. Typicalconditions for removing methyl are via use of 6M HCl at temperatures ofbetween room temperature and about 70° C.

[0167] Step L introduces an alkoxy group onto the halogenated(chloroinated) pyrimidine ring. Typical conditions are to react thechloropyrimidine with POH (where P is defined as above) at between roomand reflux temperature in the presence of a suitable base (e.g.potassium tert-butoxide).

[0168] Step M involves chlorination of pyrimidinone ring. Typicalconditions are to react with a chlorinating agent (e.g. POCl₃) atbetween room and reflux temperature, optionally in a suitable solventand optionally in the presence of from about 1 to about 2 equivalents ofa suitable additive (e.g. N,N-dimethylformamide or N,N-dimethylaniline).

[0169] Protection/deprotection strategies as appropriate may be employedsuch as are known in the literature. Suitable protecting groups for usein accordance with the invention can be found in “Protecting Groups”edited by P. J. Kocienski, Thieme, New York, 1994; and “ProtectiveGroups in Organic Synthesis” 2^(nd) edition, T. W. Greeene & P. G. M.Wutz, Wiley -lnterscience (1991).

[0170] It will be appreciated by those skilled in the art that certainprotected derivatives of compounds of formula (I), which may be madeprior to a final deprotection stage, may not possess pharmacologicalactivity as such, but may, in certain instances, be administered orallyor parenterally and thereafter metabolised in the body to form compoundsof the invention which are pharmacologically active. Such derivativesmay therefore be described as “prodrugs”. Further, certain compounds offormula (I) may act as prodrugs of other compounds of formula (I).

[0171] All protected derivatives, and prodrugs, of compounds of formula(I) are included within the scope of the invention. Examples of suitablepro-drugs for the compounds of the present invention are described inDrugs of Today, Volume 19, Number 9, 1983, pp 499-538 and in Topics inChemistry, Chapter 31, pp 306-316 and in “Design of Prodrugs” by H.Bundgaard, Elsevier, 1985, Chapter 1 (the disclosures in which documentsare incorporated herein by reference).

[0172] It will further be appreciated by those skilled in the art, thatcertain moieties, known to those skilled in the art as “pro-moieties”,for example as described by H. Bundgaard in “design of Prodrugs” (thedisclosure in which document is incorporated herein by reference) may beplaced on appropriate functionalities when such functionalities arepresent within compounds of formula (I).

[0173] Preferred prodrugs for compounds of formula (I) include:alcohols, esters, carbonate esters, hemi-esters, phosphate esters, nitroesters, sulfate esters, sulphoxides, amides, carbamates, azo-compounds,phosphamides, glycosides, ethers, acetals and ketals.

[0174] Pharmaceutically acceptable acid addition salts of the compoundswhich contain a basic centre may be prepared in a conventional manner.For example, a solution of the free base may be treated with theappropriate acid, either neat or in a suitable solvent, and theresulting salt may then be isolated either by filtration of byevaporation under vacuum of the reaction solvent. Pharmaceuticallyacceptable base addition salts can be obtained in an analogous manner bytreating a solution of a compound with the appropriate base. Both typesof salt may be formed or interconverted using ion-exchange resintechniques. The present application also includes all suitable isotopicvariations of the compounds or pharmaceutically acceptable saltsthereof. An isotopic variation of a compound or a pharmaceuticallyacceptable salt thereof is defined as one in which at least one atom isreplaced by an atom having the same atomic number but an atomic massdifferent from the atomic mass usually found in nature. Examples ofisotopes that can be incorporated into the compounds andpharmaceutically acceptable salts thereof include isotopes of hydrogen,carbon, nitrogen, oxygen, phosphorus, sulphur, fluorine and chlorinesuch as ²H, ³H, ¹³C, ¹⁴C, ¹⁵N, ¹⁷O, ¹⁸O, ³¹P, ³²P, ³⁵S, ¹⁸F and ³⁶Cl,respectively. Certain isotopic variations of the compounds andpharmaceutically acceptable salts thereof, for example, those in which aradioactive isotope such as ³H or ¹⁴C is incorporated, are useful indrug and/or substrate tissue distribution studies. Tritiated, i.e., ³H,and carbon-14, i.e., ¹⁴C, isotopes are particularly preferred for theirease of preparation and detectability. Further, substitution withisotopes such as 2 deuterium, i.e., H, may afford certain therapeuticadvantages resulting from greater metabolic stability, for example,increased in vivo half-life or reduced dosage requirements and hence maybe preferred in some circumstances. Isotopic variations of the compoundsand pharmaceutically acceptable salts thereof of this invention cangenerally be prepared by conventional procedures such as by theillustrative methods or by the preparations described in the Examplesand Preparations hereafter using appropriate isotopic variations ofsuitable reagents.

[0175] It will be appreciated by those skilled in the art that certainprotected derivatives of the compounds, which may be made prior to afinal deprotection stage, may not possess pharmacological activity assuch, but may, in certain instances, be administered orally orparenterally and thereafter metabolised in the body to form compounds ofthe invention which are pharmacologically active. Such derivatives maytherefore be described as “prodrugs”. Further, certain compounds may actas prodrugs of other compounds.

[0176] All protected derivatives, and prodrugs, of the compounds areincluded within the scope.

[0177] The present invention additionally comprises the combination of acGMP PDE₅ inhibitor compound as defined herein, wherein said combinationcan be administered by sequential, simultaneous or joint administrationof a compound with:

[0178] (1) one or more naturally occurring or synthetic prostaglandinsor esters thereof. Suitable prostaglandins for use herein includecompounds such as alprostadil, prostaglandin E₁, prostaglandin E₀, 13,14-dihydroprostaglandin E₁, prostaglandin E₂, eprostinol, naturalsynthetic and semi-synthetic prostaglandins and derivatives thereofincluding those described in U.S. Pat. No. 6,037,346 issued on Mar. 14,2000 and incorporated herein by reference, PGE₀, PGE₁, PGA₁, PGB₁, PGF₁α, 19-hydroxy PGA₁, 19-hydroxy—PGB₁, PGE₂, PGB₂, 19-hydroxy-PGA₂,19-hydroxy-PGB₂, PGE₃α, carboprost tromethamine dinoprost, tromethamine,dinoprostone, lipo prost, gemeprost, metenoprost, sulprostune, tiaprostand moxisylate; and/or

[0179] (2) one or more α-adrenergic receptor antagonist compounds alsoknown as α-adrenoceptors or α-receptors or α-blockers. Suitablecompounds for use herein include: the α-adrenergic receptors asdescribed in PCT application WO99/30697 published on Jun. 14, 1998, thedisclosures of which relating to α-adrenergic receptors are incorporatedherein by reference and include, selective α₁-adrenoceptors orα₂-adrenoceptors and non-selective adrenoceptors, suitableα₁-adrenoceptors include: phentolamine, phentolamine mesylate,trazodone, alfuzosin, indoramin, naftopidil, tamsulosin, dapiprazole,phenoxybenzamine, idazoxan, efaraxan, yohimbine, rauwolfa alkaloids,Recordati 15/2739, SNAP 1069, SNAP 5089, RS17053, SL 89.0591, doxazosin,terazosin, abanoquil and prazosin; α2-blockers from U.S. Pat. No.6,037,346 [Mar. 14, 2000] dibenarnine, tolazoline, trimazosin anddibenarnine; α-adrenergic receptors as described in U.S. Pat. Nos.4,188,390; 4,026,894; 3,511,836; 4,315,007; 3,527,761; 3,997,666;2,503,059; 4,703,063; 3,381,009; 4,252,721 and 2,599,000 each of whichis incorporated herein by reference; α₂-Adrenoceptors include:clonidine, papaverine, papaverine hydrochloride, optionally in thepresence of a cariotonic agent such as pirxamine; and/or

[0180] (3) one or more NO-donor (NO-agonist) compounds. SuitableNO-donor compounds for use herein include organic nitrates, such asmono- di or tri-nitrates or organic nitrate esters including glycerylbrinitrate (also known as nitroglycerin), isosorbide 5-mononitrate,isosorbide dinitrate, pentaerythritol tetranitrate, erythrityltetranitrate, sodium nitroprusside (SNP), 3-morpholinosydnoniminemolsidomine, S-nitroso-N-acetyl penicilliamine (SNAP)S-nitroso-N-glutathione (SNO-GLU), N-hydroxy—L-arginine, amylnitrate,linsidomine, linsidomine chlorohydrate, (SIN-1) S-nitroso—N-cysteine,diazenium diolates,(NONOates), 1,5-pentanedinitrate, L-arginene,ginseng, zizphi fructus, molsidomine, Re-2047, nitrosylated maxisylytederivatives such as NMI-678-11 and NMI-937 as described in published PCTapplication WO 0012075; and/or

[0181] (4) one or more potassium channel openers. Suitable potassiumchannel openers for use herein include nicorandil, cromokalim,levcromakalim, lemakalim, pinacidil, cliazoxide, minoxidil,charybdotoxin, glyburide, 4-amini pyridine, BaCl₂; and/or

[0182] (5) one or more dopaminergic agents, preferably apomorphine or aselective D2, D3 or D2/D3 agonist such as pramipexol and ropirinol (asclaimed in WO 0023056), L-Dopa or carbi dopa, PNU 95666 (as claimed inWO 0040226); and/or

[0183] (6) one or more vasodilator agents. Suitable vasodilator agentsfor use herein include nimodepine, pinacidil, cyclandelate, isoxsuprine,chloroprumazine, halo peridol, Rec 15/2739, trazodone; and/or

[0184] (7) one or more thromboxane A2 agonists; and/or

[0185] (8) one or more ergot alkoloids; Suitable ergot alkaloids aredescribed in U.S. Pat. No. 6,037,346 issued on Mar. 14, 2000 and includeacetergamine, i brazergoline, bromerguride, cianergoline, delorgotrile,disulergine, ergonovine maleate, ergotamine tartrate, etisulergine,lergotrile, lysergide, mesulergine, metergoline, metergotamine,nicergoline, pergolide, propisergide, proterguride, terguride; and/or

[0186] (9) one or more compounds which modulate the action of atrialnatruretic factor (also known as atrial naturetic peptide), B and C typenaturetic factors such as inhibitors or neutral endopeptidase; and/or

[0187] (10) one or more compounds which inhibit angiotensin-convertingenzyme such as enapril, and one or more combined inhibitors ofangiotensin-converting enzyme and neutral endopeptidase such asomapatrilat; and/or

[0188] (11) one or more angiotensin receptor antagonists such aslosartan; and/or

[0189] (12) one or more substrates for NO-synthase, such as L-arginine;and/or

[0190] (13) one or more calcium channel blockers such as amlodipine;and/or

[0191] (14) one or more antagonists of endothelin receptors andinhibitors or endothelin-converting enzyme; and/or

[0192] (15) one or more cholesterol lowering agents such as statins(e.g. atorvastatin/Lipitor—trade mark) and fibrates; and/or

[0193] (16) one or more antiplatelet and antithrombotic agents, e.g.tPA, uPA, warfarin, hirudin and other thrombin inhibitors, heparin,thromboplastin activating factor inhibitors; and/or

[0194] (17) one or more insulin sensitising agents such as rezulin andhypoglycaemic agents such as glipizide; and/or

[0195] (18) one or more COX 2 inhibitors; and/or

[0196] (19) pregabalene; and/or

[0197] (20) gabapentene; and/or

[0198] (21) one or more acetylcholinesterase inhibitors such asdonezipil; and/or

[0199] (22) one or more steroidal anti-inflammatory agents; and/or

[0200] (23) one or more estrogen agonists and/or estrogen antagonists,preferably raloxifene or lasofoxifene,(−)-cis-6-phenyl-5-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydronaphthalene-2-oland pharmaceutically acceptable salts thereof (compound A below) thepreparation of which is detailed in WO 96/21656.

[0201] (24) one or more one or more of a further PDE inhibitor, moreparticularly a PDE 2, 4, 7 or 8 inhibitor, preferably PDE2 inhibitor,said inhibitors preferably having an IC50 against the respective enzymeof less than 100 nM: and/or

[0202] (25) one or more of an NPY (neuropeptide Y) inhibitor, moreparticularly NPY1 or NPY5 inhibitor, preferably NPYI inhibitor,preferably said NPY inhibitors (including NPY Y1 and NPY Y5) having anIC50 of less than 100 nM , more preferably less than 50 nM, suitable NPYand in particular NPY1 inhibitor compounds are described inEP-A-1097718; and/or

[0203] (26) one or more of vasoactive intestinal peptide (VIP), VIPmimetic, more particularly mediated by one or more of the VIP receptorsubtypes VPAC1,VPAC or PACAP (pituitary adenylate cyclase activatingpeptide), one or more of a VIP receptor agonist or a VIP analogue (egRo-125-1553) or a VIP fragment, one or more of a α-adrenoceptorantagonist with VIP combination (eg lnvicorp, Aviptadil); and/or

[0204] (27) one or more of a melanocortin receptor agonist or modulatoror melanocortin ehancer, such as melanotan II, PT-14, PT-141 orcompounds claimed in WO-09964002, WO-00074679, WO-09955679, WO-00105401,WO-00058361, WO-00114879, WO-00113112, WO-09954358; and/or

[0205] (28) one or more of a serotonin receptor agonist, antagonist ormodulator, more particularly agonists, antagonists or modulators for5HT1A (including VML 670), 5HT2A, 5HT2C, 5HT3 and/or 5HT6 receptors,including those described in WO-09902159, WO-00002550 and/orWO-00028993; and/or

[0206] (29) one or more of a modulator of transporters fornoradrenaline, dopamine and/or serotonin, such as bupropion, GW-320659;and/or

[0207] (30) one or more of a purinergic receptor agonist and/ormodulator; and/or

[0208] (31) one or more of a neurokinin (NK) receptor antagonist,including those described in WO-09964008; and/or

[0209] (32) one or more of an opioid receptor agonist, antagonist ormodulator, preferably agonists for the ORL-1 receptor; and/or

[0210] (33) one or more of an agonist or modulator foroxytocin/vasopressin receptors, preferably a selective oxytocin agonistor modulator; and/or

[0211] (34) one or more modulators of cannabinoid receptors; and/or

[0212] (35) one or more of an NEP inhibitor, preferably wherein said NEPis EC 3.4.24.11 and more preferably wherein said NEP inhibitor is aselective inhibitor for EC_(3.4.24.11), more preferably a selective NEPinhibitor is a selective inhibitor for EC_(3.4.24.11), which has an IC50of less than 100 nM (e.g. ompatrilat, sampatrilat) suitable NEPinhibitor compounds are described in EP-A-1097719; and/or

[0213] (36) one or more compounds which inhibit angiotensin-convertingenzyme such as enalapril, and one or more combined inhibitors ofangiotensin-converting enzyme and neutral endopeptidase such asomapatrilat; and/or

[0214] (37) one or more tricyclic antidepressants, e.g. amitriptiline;and/or

[0215] (38) one or more non-steroidal anti-inflammatory agents; and/or

[0216] (39) one or more angiotensin-converting enzyme (ACE) inhibitors,e.g. quinapril; and/or

[0217] (40) one or more anti-depressants (such as clomipramine and SSRIs(such as paroxetine and sertaline).

[0218] wherein said combination can be in the form of co-administration,simultaneous administration, concurrent administration, or stepwiseadministration.

[0219] Medical Use

[0220] The compounds of the invention are useful because they possesspharmacological activity in animals, especially mammals, includinghumans. They are therefore indicated as pharmaceuticals, as well as foruse as animal medicaments.

[0221] According to a further aspect of the invention there is providedthe compounds of the invention for use as pharmaceuticals, and for useas animal medicaments.

[0222] In particular, compounds of the invention have been found to bepotent and selective inhibitors of cGMP PDEs, such as cGMP PDE5, forexample as demonstrated in the tests described below, and are thususeful in the treatment of medical conditions in humans, and in animals,in which cGMP PDEs, such as cGMP PDE5, are indicated, and in whichinhibition of cGMP PDEs, such as cGMP PDE5, is desirable.

[0223] By the term “treatment”, we include both therapeutic (curative),palliative or prophylactic treatment.

[0224] Thus, according to a further aspect of the invention there isprovided the use of the compounds of the invention in the manufacture ofa medicament for the treatment of a medical condition in which a cGMPPDE (e.g. cGMP PDE5) is indicated. There is further provided the use ofthe compounds of the invention in the manufacture of a medicament forthe treatment of a medical condition in which inhibition of a cGMP PDE(e.g. cGMP PDE5) is desirable.

[0225] The compounds of the invention are thus expected to be useful forthe curative, palliative or prophylactic treatment of mammalian sexualdisorders. In particular, the compounds are of value in the treatment ofmammalian sexual dysfunctions such as male erectile dysfunction (MED),impotence, female sexual dysfunction (FSD), clitoral dysfunction, femalehypoactive sexual desire disorder, female sexual arousal disorder,female sexual pain disorder or female sexual orgasmic dysfunction (FSOD)as well as sexual dysfunction due to spinal cord injury or selectiveserotonin re-uptake inhibitor (SSRI) induced sexual dysfunction but,clearly, will be useful also for treating other medical conditions forwhich a potent and selective cGMP PDE5 inhibitor is indicated. Suchconditions include premature labour, dysmenorrhoea, benign prostatichyperplasia (BPH), bladder outlet obstruction, incontinence, stable,unstable and variant (Prinzmetal) angina, hypertension, pulmonaryhypertension, chronic obstructive pulmonary disease, coronary arterydisease, congestive heart failure, atherosclerosis, conditions ofreduced blood vessel patency, e.g. post-percutaneous transluminalcoronary angioplasty (post-PTCA), peripheral vascular disease, stroke,nitrate induced tolerance, bronchitis, allergic asthma, chronic asthma,allergic rhinitis, diseases and conditions of the eye such as glaucoma,optic neuropathy, macular degeneration, elevated intra-occular pressure,retinal or arterial occulsion and diseases characterised by disorders ofgut motility, e.g. irritable bowel syndrome (IBS).

[0226] Further medical conditions for which a potent and selective cGMPPDE5 inhibitor is indicated, and for which treatment with compounds ofthe present invention may be useful, include pre-eclampsia, Kawasaki'ssyndrome, nitrate tolerance, multiple sclerosis, diabetic nephropathy,neuropathy including autonomic and peripheral neuropathy and inparticular diabetic neuropathy and symptoms thereof (e.g.gastroparesis), peripheral diabetic neuropathy, Alzheimer's disease,acute respiratory failure, psoriasis, skin necrosis, cancer, metastasis,baldness, nutcracker oesophagus, anal fissure, haemorrhoids, hypoxicvasoconstriction, hypoxic vasoconstriction, diabetes, type 2 diabetesmellitus, the insulin resistance syndrome, insulin resistance, impairedglucose tolerance, as well as the stabilisation of blood pressure duringhaemodialysis.

[0227] Particularly preferred conditions include MED and FSD.

[0228] Thus, the invention provides a method of treating or preventing amedical condition for which a cGMP PDE5 inhibitor is indicated, in ananimal (e.g. a mammal, including a human being), which comprisesadministering a therapeutically effective amount of a compound of theinvention to a mammal in need of such treatment.

[0229] Pharmaceutical Preparations

[0230] The compounds will normally be administered orally or by anyparenteral route, in the form of pharmaceutical preparations comprisingthe active ingredient, optionally in the form of a non-toxic organic, orinorganic, acid, or base, addition salt, in a pharmaceuticallyacceptable dosage form. Depending upon the disorder and patient to betreated, as well as the route of administration, the compositions may beadministered at varying doses.

[0231] The compounds may also be combined with any other drugs useful inthe inhibition of cGMP-PDEs, such as cGMP-PDE5.

[0232] The compounds, their pharmaceutically acceptable salts, andpharmaceutically acceptable solvates of either entity can beadministered alone but, in human therapy will generally be administeredin admixture with a suitable pharmaceutical excipient diluent or carrierselected with regard to the intended route of administration andstandard pharmaceutical practice.

[0233] For example, the compounds or salts or solvates thereof can beadministered orally, buccally or sublingually in the form of tablets,capsules (including soft gel capsules), ovules, elixirs, solutions orsuspensions, which may contain flavouring or colouring agents, forimmediate-, delayed-, modified-, or controlled-release such assustained-, dual-, or pulsatile delivery applications. The compounds mayalso be administered via intracavernosal injection. The compounds mayalso be administered via fast dispersing or fast dissolving dosagesforms.

[0234] Such tablets may contain excipients such as microcrystallinecellulose, lactose, sodium citrate, calcium carbonate, dibasic calciumphosphate, glycine and starch (preferably corn, potato or tapiocastarch), disintegrants such as sodium starch glycollate, croscarmellosesodium and certain complex silicates, and granulation binders such aspolyvinylpyrrolidone, hydroxypropylmethyl cellulose (HPMC),hydroxypropylcellulose (HPC), sucrose, gelatin and acacia. Additionally,lubricating agents such as magnesium stearate, stearic acid, glycerylbehenate and talc may be included.

[0235] Solid compositions of a similar type may also be employed asfillers in gelatin capsules. Preferred excipients in this regard includelactose, starch, a cellulose, milk sugar or high molecular weightpolyethylene glycols. For aqueous suspensions and/or elixirs, thecompounds of the invention may be combined with various sweetening orflavouring agents, colouring matter or dyes, with emulsifying and/orsuspending agents and with diluents such as water, ethanol, propyleneglycol and glycerin, and combinations thereof.

[0236] Modified release and pulsatile release dosage forms may containexcipients such as those detailed for immediate release dosage formstogether with additional excipients that act as release rate modifiers,these being coated on and/or included in the body of the device. Releaserate modifiers include, but are not exclusively limited to,hydroxypropylmethyl cellulose, methyl cellulose, sodiumcarboxymethylcellulose, ethyl cellulose, cellulose acetate, polyethyleneoxide, Xanthan gum, Carbomer, ammonio methacrylate copolymer,hydrogenated castor oil, carnauba wax, paraffin wax, cellulose acetatephthalate, hydroxypropylmethyl cellulose phthalate, methacrylic acidcopolymer and mixtures thereof. Modified release and pulsatile releasedosage forms may contain one or a combination of release rate modifyingexcipients. Release rate modifying excipients maybe present both withinthe dosage form i.e. within the matrix, and/or on the dosage form i.e.upon the surface or coating.

[0237] Fast dispersing or dissolving dosage formulations (FDDFs) maycontain the following ingredients: aspartame, acesulfame potassium,citric acid, croscarmellose sodium, crospovidone, diascorbic acid, ethylacrylate, ethyl cellulose, gelatin, hydroxypropyimethyl cellulose,magnesium stearate, mannitol, methyl methacrylate, mint flavouring,polyethylene glycol, fumed silica, silicon dioxide, sodium starchglycolate, sodium stearyl fumarate, sorbitol, xylitol. The termsdispersing or dissolving as used herein to describe FDDFs are dependentupon the solubility of the drug substance used i.e. where the drugsubstance is insoluble a fast dispersing dosage form can be prepared andwhere the drug substance is soluble a fast dissolving dosage form can beprepared.

[0238] The compounds can also be administered parenterally, for example,intracavernosally, intravenously, intra-arterially, intraperitoneally,intrathecally, intraventricularly, intraurethrally intrasternally,intracranially, intramuscularly or subcutaneously, or they may beadministered by infusion techniques. For such parenteral administrationthey are best used in the form of a sterile aqueous solution which maycontain other substances, for example, enough salts or glucose to makethe solution isotonic with blood. The aqueous solutions should besuitably buffered (preferably to a pH of from 3 to 9), if necessary. Thepreparation of suitable parenteral formulations under sterile conditionsis readily accomplished by standard pharmaceutical techniques well-knownto those skilled in the art.

[0239] For oral and parenteral administration to human patients, thedaily dosage level of the compounds or salts or solvates thereof willusually be from 10 to 500 mg (in single or divided doses).

[0240] Thus, for example, tablets or capsules of the compounds or saltsor solvates thereof may contain from 5 mg to 250 mg of active compoundfor administration singly or two or more at a time, as appropriate. Thephysician in any event will determine the actual dosage which will bemost suitable for any individual patient and it will vary with the age,weight and response of the particular patient. The above dosages areexemplary of the average case. There can, of course, be individualinstances where higher or lower dosage ranges are merited and such arewithin the scope of this invention. The skilled person will alsoappreciate that, in the treatment of certain conditions (including MEDand FSD), compounds may be taken as a single dose on an “as required”basis (i.e. as needed or desired).

[0241] Example Tablet Formulation

[0242] In general a tablet formulation could typically contain betweenabout 0.01 mg and 500 mg of the compound (or a salt thereof) whilsttablet fill weights may range from 50 mg to 1000 mg. An exampleformulation for a 10 mg tablet is illustrated: Ingredient % w/w “Active”Compound 10.000* Lactose 64.125 Starch 21.375 Croscarmellose Sodium 3.000 Magnesium Stearate  1.500

[0243] Such tablets can be manufactured by standard processes, forexample, direct compression or a wet or dry granulation process. Thetablet cores may be coated with appropriate overcoats.

[0244] The compounds can also be administered intranasally or byinhalation and are conveniently delivered in the form of a dry powderinhaler or an aerosol spray presentation from a pressurised container,pump, spray or nebuliser with the use of a suitable propellant, e.g.dichlorodifluoromethane, trichlorofluoromethane,dichlorotetrafluoroethane, a hydrofluoroalkane such as1,1,1,2-tetrafluoroethane (HFA 134A [trade mark] or1,1,1,2,3,3,3-heptafluoropropane (HFA 227EA [trade mark]), carbondioxide or other suitable gas. In the case of a pressurised aerosol, thedosage unit may be determined by providing a valve to deliver a meteredamount. The pressurised container, pump, spray or nebuliser may containa solution or suspension of the active compound, e.g. using a mixture ofethanol and the propellant as the solvent, which may additionallycontain a lubricant, e.g. sorbitan trioleate. Capsules and cartridges(made, for example, from gelatin) for use in an inhaler or insufflatormay be formulated to contain a powder mix of the compound and a suitablepowder base such as lactose or starch.

[0245] Aerosol or dry powder formulations are preferably arranged sothat each metered dose or “puff” contains from 1 to 50 mg of thecompound for delivery to the patient. The overall daily dose with anaerosol will be in the range of from 1 to 50 mg which may beadministered in a single dose or, more usually, in divided dosesthroughout the day.

[0246] The compounds may also be formulated for delivery via anatomiser. Formulations for atomiser devices may contain the followingingredients as solubilisers, emulsifiers or suspending agents: water,ethanol, glycerol, propylene glycol, low molecular weight polyethyleneglycols, sodium chloride, fluorocarbons, polyethylene glycol ethers,sorbitan trioleate, oleic acid.

[0247] Alternatively, the compounds or salts or solvates thereof can beadministered in the form of a suppository or pessary, or they may beapplied topically in the form of a gel, hydrogel, lotion, solution,cream, ointment or dusting powder. The compounds or salts or solvatesthereof may also be dermally administered. The compounds or salts orsolvates thereof may also be transdermally administered, for example, bythe use of a skin patch. They may also be administered by the ocular,pulmonary or rectal routes.

[0248] For ophthalmic use, the compounds can be formulated as micronisedsuspensions in isotonic, pH adjusted, sterile saline, or, preferably, assolutions in isotonic, pH adjusted, sterile saline, optionally incombination with a preservative such as a benzylalkonium chloride.Alternatively, they may be formulated in an ointment such as petrolatum.

[0249] For application topically to the skin, the compounds or salts orsolvates thereof can be formulated as a suitable ointment containing theactive compound suspended or dissolved in, for example, a mixture withone or more of the following: mineral oil, liquid petrolatum, whitepetrolatum, propylene glycol, polyoxyethylene polyoxypropylene compound,emulsifying wax and water. Alternatively, they can be formulated as asuitable lotion or cream, suspended or dissolved in, for example, amixture of one or more of the following: mineral oil, sorbitanmonostearate, a polyethylene glycol, liquid paraffin, polysorbate 60,cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol andwater.

[0250] The compounds may also be used in combination with acyclodextrin. Cyclodextrins are known to form inclusion andnon-inclusion complexes with drug molecules. Formation of adrug-cyclodextrin complex may modify the solubility, dissolution rate,bioavailability and/or stability property of a drug molecule.Drug-cyclodextrin complexes are generally useful for most dosage formsand administration routes. As an alternative to direct complexation withthe drug the cyclodextrin may be used as an auxiliary additive, e.g. asa carrier, diluent or solubiliser. Alpha-, beta- and gamma-cyclodextrinsare most commonly used and suitable examples are described inWO-A-91/11172, WO-A-94/02518 and WO-A-98/55148.

[0251] Generally, in humans, oral administration of the compounds is thepreferred route, being the most convenient and, for example in MED,avoiding the well-known disadvantages associated with intracavernosal(i.c.) administration. A preferred oral dosing regimen in MED for atypical man is from 25 to 250 mg of compound when required. Incircumstances where the recipient suffers from a swallowing disorder orfrom impairment of drug absorption after oral administration, the drugmay be administered parenterally, sublingually or buccally.

[0252] For veterinary use, the compound, or a veterinarily acceptablesalt thereof, or a veterinarily acceptable solvate or pro-drug thereof,is administered as a suitably acceptable formulation in accordance withnormal veterinary practice and the veterinary surgeon will determine thedosing regimen and route of administration which will be mostappropriate for a particular animal.

[0253] Thus, according to a further aspect there is provided apharmaceutical formulation including a compound as detailed hereinbeforein admixture with a pharmaceutically or veterinarily acceptableadjuvant, diluent or carrier.

[0254] In addition to the fact that the compounds inhibit cyclicguanosine 3′,5′-monophosphate phosphodiesterases (cGMP PDEs) and inparticular, are potent and selective inhibitors of cGMP PDE5, thecompounds may also have the advantage that they may be more efficaciousthan, be less toxic than, have a broader range of activity than, be morepotent than, produce fewer side effects than, be more easily absorbedthan, or they may have other useful pharmacological properties over,compounds known in the prior art.

[0255] Bioavailability

[0256] Preferably the compounds of the invention are orallybioavailable. Oral bioavailablity refers to the proportion of an orallyadministered drug that reaches the systemic circulation. The factorsthat determine oral bioavailability of a drug are dissolution, membranepermeability and metabolic stability. Typically, a screening cascade offirstly in vitro and then in vivo techniques is used to determine oralbioavailablity.

[0257] Dissolution, the solubilisation of the drug by the aqueouscontents of the gastro-intestinal tract (GIT), can be predicted from invitro solubility experiments conducted at appropriate pH to mimic theGIT. Preferably the compounds of the invention have a minimum solubilityof 50 mcg/ml. Solubility can be determined by standard procedures knownin the art such as described in Adv. Drug Deliv. Rev. 23, 3-25, 1997.

[0258] Membrane permeability refers to the passage of the compoundthrough the cells of the GIT. Lipophilicity is a key property inpredicting this and is defined by in vitro Log D_(7.4) measurementsusing organic solvents and buffer. Preferably the compounds of theinvention have a Log D_(7.4) of −2 to +4, more preferably −1 to +2. Thelog D can be determined by standard procedures known in the art such asdescribed in J. Pharm. Pharmacol. 1990, 42:144.

[0259] Cell monolayer assays such as CaCo₂ add substantially toprediction of favourable membrane permeability in the presence of effluxtransporters such as p-glycoprotein, so-called caco-2 flux. Preferably,compounds of the invention have a caco-2 flux of greater than 2×10⁻⁶cms⁻¹, more preferably greater than 5×10⁻⁶ cms⁻¹. The caco flux valuecan be determined by standard procedures known in the art such asdescribed in J. Pharm. Sci, 1990, 79, 595-600.

[0260] Metabolic stability addresses the ability of the GIT or the liverto metabolise compounds during the absorption process: the first passeffect. Assay systems such as microsomes, hepatocytes etc are predictiveof metabolic liability. Preferably the compounds of the Examples showmetabolic stablity in the assay system that is commensurate with anhepatic extraction of less then 0.5. Examples of assay systems and datamanipulation are described in Curr. Opin. Drug Disc. Devel., 201, 4,36-44, Drug Met. Disp.,2000, 28, 1518-1523.

[0261] Because of the interplay of the above processes further supportthat a drug will be orally bioavailable in humans can be gained by invivo experiments in animals. Absolute bioavailability is determined inthese studies by administering the compound separately or in mixtures bythe oral route. For absolute determinations (% absorbed) the intravenousroute is also employed. Examples of the assessment of oralbioavailability in animals can be found in Drug Met. Disp., 2001, 29,82-87; J. Med Chem , 1997, 40, 827-829, Drug Met. Disp., 1999, 27,221-226.

[0262] The biological activities of the compounds were determined by thefollowing test methods.

[0263] Phosphodiesterase (PDE) Inhibitory Activity

[0264] The compounds of the present invention are potent and selectivecGMP PDE5 inhibitors. In vitro PDE inhibitory activities against cyclicguanosine 3′,5′-monophosphate (cGMP) and cyclic adenosine3′,5′-monophosphate (cAMP) phosphodiesterases were determined bymeasurement of their IC₅₀ values (the concentration of compound requiredfor 50% inhibition of enzyme activity).

[0265] The required PDE enzymes were isolated from a variety of sources,including human corpus cavernosum, human platelets, human cardiacventricle, human skeletal muscle and human and canine retina,essentially by the method of W. J. Thompson and M. M. Appleman(Biochem., 1971, 10, 311). In particular, the cGMP-specific PDE (PDE5)and the cGMP-inhibited cAMP PDE (PDE3) were obtained from human corpuscavernosum tissue or human platelets; the cGMP-stimulated PDE (PDE2) wasobtained from human corpus cavernosum or human platelets; thecalcium/calmodulin (Ca/CAM)-dependent PDE (PDE1) from human cardiacventricle; the cAMP-specific PDE (PDE4) from recombinant clone or humanskeletal muscle; and the photoreceptor PDE (PDE6) from canine or humanretina. Phosphodiesterases 7-11 were generated from full length humanrecombinant clones transfected into SF9 cells.

[0266] Assays were performed either using a modification of the “batch”method of W. J. Thompson et al. (Biochem., 1979, 18, 5228) or using ascintillation proximity assay for the direct detection of AMP/GMP usinga modification of the protocol described by Amersham plc under productcode TRKQ7090/7100. In summary, the effect of PDE inhibitors wasinvestigated by assaying a fixed amount of enzyme in the presence ofvarying inhibitor concentrations and low substrate, (cGMP or cAMP in a3:1 ratio unlabelled to [³H]-labeled at a conc ˜1/2 K_(m)) such thatIC₅₀≅K_(i). The final assay volume was made up to 102 μl with assaybuffer [20 mM Tris-HCl pH 7.4, 5 mM MgCl₂, 1 mg/ml bovine serumalbumin]. Reactions were initiated with enzyme, incubated for 30-60 minat 30° C. to give <30% substrate turnover and terminated with 50 μlyttrium silicate SPA beads (containing 3 mM of the respective unlabelledcyclic nucleotide for PDEs 3, 9 and 11). Plates were re-sealed andshaken for 20 min, after which the beads were allowed to settle for 30min in the dark and then counted on a TopCount plate reader (Packard,Meriden, Conn.). Radioactivity units were converted to % activity of anuninhibited control (100%), plotted against inhibitor concentration andinhibitor IC₅₀ values obtained using the ‘Fit Curve’ Microsoft Excelextension or in-house equivalent. Results from these tests show that thecompounds of the present invention are potent and selective inhibitorsof cGMP-specific PDE5.

[0267] Preferred compounds of formula (I) herein have IC₅₀ values ofless than or equal to about 30 nM for the PDE5 enzyme. A more preferredgroup of compounds have IC₅₀ values of less than or equal to about 10 nMfor the PDE5 enzyme. An additional group of compounds having IC₅₀ valuesof less than about 5 nM for the PDE5 enzyme are further preferred.

[0268] Especially preferred herein are compounds which have an IC₅₀value of less than about 10, more preferably less than about 5 nM forthe PDE5 enzyme in combination with greater than 10-fold selectivity forthe PDE5 enzyme versus the PDE6 enzyme. Highly preferred are compoundshaving IC₅₀ values of less than about 10, more preferably less thanabout 5 nM for the PDE5 enzyme in combination with greater than 20-fold,preferably greater than 30-fold and especially greater than 40-foldselectivity for the PDE5 enzyme versus the PDE6 enzyme.

[0269] Functional Activity

[0270] This was assessed in vitro by determining the capacity of acompound of the invention to enhance sodium nitroprusside-inducedrelaxation of pre-contracted rabbit corpus cavernosum tissue strips, asdescribed by S. A. Ballard et al. (Brit. J. Pharmacol., 1996, 118(suppl.), abstract 153P).

[0271] In vivo Activity

[0272] In vivo activity is tested by screening test compounds inanaesthetised dogs to determine their capacity, after i.v.administration, to enhance the pressure rises in the corpora cavernosaof the penis induced by intracavernosal injection of sodiumnitroprusside, using a method based on that described by Trigo-Rocha etal. (Neurourol. and Urodyn., 1994, 13, 71).

[0273] Safety Profile

[0274] The compounds may be tested at varying i.v and p.o. doses inanimals such as mouse and dog, observing for any untoward effects.

[0275] Biological Activity

[0276] Table 1 illustrates the in vitro cGMP PDE5 inhibitory activitiesfor a range of compounds of the invention. TABLE 1 Example PDE5 IC₅₀(nM) PDE6 IC₅₀ (nM) 13 11.9 609 2 13.8 592 3 23.0 922 12 1.8 163 6 2.285 10 3.2 152

EXAMPLES AND PREPARATIONS

[0277] The synthesis of the compounds of general formula (I) and of theintermediates for use therein can be achieved by analogy with theprocesses of the Examples and Preparations hereinafter.

[0278]¹H nuclear magnetic resonance (NMR) spectra were recorded usingeither a Varian Unity 300 or a Varian inova 400 spectrometer and were inall cases consistent with the proposed structures. Characteristicchemical shifts (δ) are given in parts-per-million downfield fromtetramethylsilane using conventional abbreviations for designation ofmajor peaks: e.g. s, singlet; d, doublet; t, triplet; q, quartet; m,multiplet; br, broad.

[0279] Mass spectra (m/z) were recorded using a Fisons Instruments Triomass spectrometer in the thermospray ionisation mode (TSP) or using aFinnigan navigator in electrospray ionisation mode (ES)—positive and/ornegative ionisation mode.

[0280] As used herein, the term “column chromatography” refers to normalphase chromatography using silica gel (0.04-0.06 mm).

[0281] Room temperature includes 20 to 25° C.

Example 15-(5-Acetyl-2-butoxyphenyl)-2-(1-cyclobutyl-3-azetidinyl)-3-ethyl-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one

[0282]

[0283] A solution of the azetidine from preparation 14 (500 mg, 0.785mmol) and cyclobutanone (176 μl, 2.36 mmol) in dichloromethane (4 ml)was stirred at room temperature for 10 minutes, them sodiumtriacetoxyborohydride (419 mg, 1.86 mmol) added, and the reactionmixture stirred at room temperature for 3 hours. The mixture was dilutedwith dichloromethane (25 ml) and washed with water and sodiumbicarbonate solution. The combined aqueous solutions were extracted withdichloromethane (2×25 ml), and the combined organic solutions thenwashed with brine, dried (MgSO₄) and concentrated under reducedpressure. The crude product was purified by column chromatography onsilica gel using dichloromethane:methanol (97.5:2.5) as eluant to givean oil. This was crystallised from diethyl ether, to afford the titlecompound as a white solid, 210 mg. ¹H NMR (CDCl₃, 400 MHz) δ: 1.00 (t,3H), 1.38 (t, 3H), 1.57 (m, 2H), 1.66-1.99 (m, 6H), 2.04 (m, 2H), 2.62(s, 3H), 3.02 (q, 2H), 3.34 (m, 1H), 3.80 (d, 4H), 4.25 (t, 2H), 5.16(m, 1H), 7.11 (d, 1H), 8.06 (dd, 1H), 8.95 (d, 1H), 10.54 (s, 1H).

[0284] LRMS: m/z (TSP⁺) 464.2 [MH⁺]

[0285] Microanalysis found: C, 66.88; H, 7.30; N, 14.85. C₂₆H₃₃N₅O₃;0.05H₂O requires C, 67.23; H, 7.18; N, 15.08%.

Examples 2 to 4

[0286] The following compounds of general formula:

[0287] were prepared from the appropriate azetidine compounds(preparations 14 and 15) and ketones, following similar procedures tothat described in example 1. Yield Ex R³ R^(x) (%) Data 2

50 white solid ¹H NMR(CDCl₃, 400 MHz) δ: 1.08(d, 6H), 1.36(t, 3H),1.63-1.92(m, 4H), 2.01(m, 2H), 2.26(m, 1H), 2.60(s, 3H), 3.00(q, 2H),3.30(m, 1H), 3.79(d, 4H), 4.00(d, 2H), 5.15(m, 1H), 7.05(d, 1H), 8.02(d,1H), 8.88(s, 1H), 10.48(s, 1H). LRMS: m/z(TSP⁺) 464.2[MH⁺] #Microanalysis found: C, 66.24; H, 7.34; N, 14.43. C₂₆H₃₃N₅O₃; 0.5H₂Orequires C, 66.08; H, 7.25; N, 14.82%. 3¹

18 white solid ¹H NMR(CDCl₃, 400 MHz) δ: 1.01(m, 9H), 1.39(t, 3H),1.58(m, 2H), 1.98(m, 2H), 2.62(m, 4H), 3.02(q, 2H), 3.78(dd, 2H),3.92(dd, 2H), 4.28(t, 2H), 5.15(m, 1H), 7.10(d, 1H), 8.08(dd, 1H),8.98(d, 1H), 10.55(s, 1H). LRMS: m/z(TSP⁺) 452.2[MH⁺]Microanalysisfound: C, 65.97; H, # 7.37; N, 15.36. C₂₅H₃₃N₅O₃; 0.25H₂O requires C,65.84; H, 7.40; N, 15.36%. 4¹

38 white solid ¹H NMR(CDCl₃, 400 MHz) δ: 1.00(d, 6H), 1.10(d, 6H),1.38(t, 3H), 2.30(m, 1H), 2.61(m, 4H), 3.01(q, 2H), 3.78(dd, 2H),3.90(dd, 2H), 4.02(d, 2H), 5.15(m, 1H), 7.09(d, 1H), 8.05(dd, 1H),8.94(d, 1H), 10.50(s, 1H). LRMS: m/z 452.1[MH⁺]Microanalysis found: C,65.32; H, # 7.36; N, 14.92. C₂₆H₃₃N₅O₃; 0.5H₂O requires C, 66.08; H,7.25; N, 14.82%.

Example 5tert-Butyl-5-[(5-acetyl-2-propoxyphenyl)-3-ethyl-7-oxo-6,7-dihydro-1H-pyrazolo[4,3-dpyrimidin-1-yl]-acetateand Example 6tert-Butyl-5-r(5-acetyl-2-propoxyphenyl)-3-ethyl-7-oxo-6,7-dihydro-2H-pyrazolo[4,3-d]pyrimidin-2-yl]-acetate

[0288]

[0289] tert-Butyl bromoacetate (295 μl, 2 mmol) was added to asuspension of cesium carbonate (652 mg, 2 mmol) and the pyrazole frompreparation 17 (680 mg, 2 mmol) in N,N-dimethylformamide (15 ml) at roomtemperature, and the reaction was stirred for 18 hours. The mixture wasquenched with water and extracted with diethyl ether (5×30 ml) and ethylacetate (3×20 ml). The diethyl ether extracts were dried over Na₂SO₄,concentrated under reduced pressure and purified by columnchromatography on silica gel using dichloromethane:methanol:0.88 ammonia(95:5:0.5) and the product was recrystallised fromdichloromethane/diisopropylether to afford the title compound of example5 as a white solid, 171 mg.

[0290]¹H NMR (CDCl₃, 400 MHz) δ: 1.19 (t, 3H), 1.47 (m, 12H), 2.03 (m,2H), 2.68 (s, 3H), 3.06 (q, 2H), 4.26 (t, 2H), 5.24 (s, 2H), 7.14 (d,1H), 8.13 (d, 1H), 9.07 (s, 1H), 10.92 (br s, 1H).

[0291] LRMS: m/z (TSP⁺) 455.7 [MH⁺].

[0292] Microanalysis found: C, 63.29; H, 6.66; N, 12.24. C₂₄H₃₀N₄O₅requires C, 63.42; H, 6.65; N, 12.33%.

[0293] The ethyl acetate extracts were dried over Na₂SO₄, concentratedunder reduced pressure and purified by column chromatography on silicagel using dichloromethane:methanol:0.88 ammonia (95:5:0.5) as eluant andthe product was recrystallised from dichloromethane/diisopropylether toafford the title compound of example 6 as a white solid, 112 mg.

[0294]¹H NMR (CDCl₃, 400 MHz) δ: 1.17 (t, 3H), 1.46 (m, 12H), 2.02 (m,2H), 2.66 (s, 3H), 3.01 (q, 2H), 4.24 (t, 2H), 5.03 (s, 2H), 7.14 (d,1H), 8.09 (d, 1H), 8.99 (s, 1H), 10.60 (br s, 1H).

[0295] LRMS: m/z (TSP⁺) 455.4 [MH⁺].

[0296] Microanalysis found: C, 62.96; H, 6.65; N, 12.21. C₂₄H₃₀N₄O₅requires C, 63.42; 15H, 6.65; N, 12.33%.

Example 7tert-Butyl-3-[(5-acetyl-2-propoxyphenyl)-3-ethyl-7-oxo-6,7-dihydro-1H-pyrazolo[4,3-d]pyrimidin-1-yl]-2-methylpropanoate

[0297]

[0298] 2-Bromo-tert-butylisobutyrate (446 mg, 2 mmol) was added to asuspension of cesium carbonate (652 mg, 2 mmol) and the pyrazole frompreparation 17 (680 mg, 2 mmol) in N,N-dimethylformamide (15 ml) at roomtemperature, and the reaction was stirred for 18 hours. Startingmaterial remained by TLC analysis, so the reaction was heated to 60° C.for 36 hours, cooled to room temperature and quenched with water (50ml). The mixture was extracted with diethyl ether (3×50 ml) and thecombined organic extracts were dried over Na₂SO₄, concentrated underreduced pressure and purified by column chromatography on silica gelusing dichloromethane:methanol:0.88 ammonia (95:5:0.5) as eluant and theproduct was recrystallised from diisopropylether to afford the titlecompound as a white solid, 55 mg.

[0299]¹H NMR (CDCl₃, 300 MHz) δ: 1.17 (m, 6H), 1.44 (m, 12H), 2.02 (m,2H), 2.66 (s, 3H), 3.12 (q, 2H), 3.38 (m, 1H), 4.22 (m, 3H), 4.60 (dd,1H), 7.13 (d, 1H), 8.08 (d, 1H), 9.00 (s,1H), 10.60 (br s, 1H).

[0300] LRMS: m/z (TSP⁺) 483.3 [MH⁺].

[0301] Microanalysis found: C, 64.44; H, 7.09; N, 11.63. C₂₆H₃₄N₄O₅requires C, 64.70; H, 7.10; N, 11.61%.

Example 8 Ethyl2-[5-(5-acetyl-2-propoxyphenyl)-3-ethyl-7-oxo-6,7-dihydro-2H-pyrazolo[4,3-d]pyrimidin-2-yl]propanoate

[0302]

[0303] Ethyl-2-bromopropanoate (362 mg, 2 mmol) was added to asuspension of cesium carbonate (652 mg, 2 mmol) and the pyrazole frompreparation 17 (680 mg, 2 mmol) in N,N-dimethylformamide (15 ml) at roomtemperature, and the reaction was stirred at 60° C. for 13 hours, cooledto room temperature and quenched with water (50 ml). The mixture wasextracted with diethyl ether (3×50 ml) and ethyl acetate (3×50 ml) andthe combined organic extracts were dried over Na₂SO₄, concentrated underreduced pressure and purified by column chromatography on silica gelusing dichloromethane:methanol:0.88 ammonia (97.5:2.5:0.25) as eluant.This gave two products, the most polar of which was crystallised fromdiisopropylether to afford the title compound as a white solid, 98 mg.

[0304]¹H NMR (CDCl₃, 300 MHz) δ: 1.13 (t, 3H), 1.23 (t, 3H), 1.43 (t,3H), 2.00 (m, 5H), 2.65 (s, 3H), 3.05 (q, 2H), 4.21 (m, 4H), 5.21 (m,1H), 7.10 (d, 1H), 8.08 (d, 1H), 8.98 (s, 1H), 10.55 (brs, 1H).

[0305] LRMS: m/z (ESP⁺) 441 [MH⁺], 463 [MNa⁺].

[0306] Microanalysis found: C, 62.53; H, 6.39; N, 12.66. C₂₃H₂₈N₄O₅requires C, 62.71; H, 6.41; N, 12.66%.

Example 9Methyl-4-[5-(5-acetyl-2-propoxyphenyl)-3-ethyl-7-oxo-6,7-dihydro-1H-pyrazolo[4,3-d]pyrimidin-1-yl]-butanoateand Example 10Methyl-4-[5-(5-acetyl-2-propoxyphenyl)-3-ethyl-7-oxo-6,7-dihydro-2H-pyrazolo[4,3-d]pyrimidin-1-yl]-butanoate

[0307]

[0308] Methyl 4-bromobutanoate (370 mg, 2 mmol) was added to asuspension of cesium carbonate (652 mg, 2 mmol) and the pyrazole frompreparation 17 (680 mg, 2 mmol) in N,N-dimethylformamide (15ml) at roomtemperature, and the reaction was stirred for 64 hours. The mixture wasquenched with water and extracted with diethyl ether (4×20 ml) and ethylacetate (2×20 ml). The ethyl acetate extracts were washed with water(2×20 ml), brine, dried over Na₂SO₄ and concentrated under reducedpressure. The residue was purified by column chromatography on silicagel using dichloromethane:methanol:0.88 ammonia (97.5:2.5:0.25) and theleast polar fraction was collected and recrystallised twice fromacetonitrile to afford the title compound of example 9 as a white solid,31 mg.

[0309]¹H NMR (CDCl₃, 400 MHz) δ: 1.19 (t, 3H), 1.43 (t, 3H), 2.04 (m,2H), 2.28 (m, 2H), 2.39 (m, 2H), 2.66 (s, 3H), 3.01 (q, 2H), 3.65 (s,3H), 4.27 (t, 2H), 4.66 (t, 2H), 7.15 (d, 1H), 8.14 (d, 1H), 9.08 (s,1H), 10.91 (brs, 1H).

[0310] LRMS: m/z(ESP⁺)441 [MH⁺], 439 [MH⁻].

[0311] Microanalysis found: C, 62.21; H, 6.45; N, 12.51. C₂₃H₂₈N₄O₅. 0.2mol H₂O requires C, 62.21; H, 6.45; N, 12.62%.

[0312] The other fractions were combined and re-chromatographed elutingwith pentane:isopropyl alcohol:0.88 ammonia (80:20:1.5). This gave twomajor products, the most polar of which was triturated withdiisopropylether to afford the title compound of example 10 as a whitesolid, 12.4 mg.

[0313]¹H NMR (CDCl₃, 300 MHz) δ: 1.16 (t, 3H), 1.45 (t, 3H), 2.01 (m,2H), 2.34 (m, 2H), 2.42 (m, 2H), 2.66 (s, 3H), 3.06 (q, 2H), 3.70 (s,3H), 4.24 (t, 2H), 4.40 (t, 2H), 7.13 (d, 1H), 8.10 (d, 1H), 8.99 (s,1H), 10.59 (brs, 1H).

[0314] LRMS: m/z (ESP⁺) 441 [MH⁺], 463 [MNa⁺], 439 [MH⁻].

[0315] Microanalysis found: C, 62.24; H, 6.37; N, 12.57. C₂₃H₂₈N₄O₅requires C, 62.71; H, 6.41; N, 12.72%.

Example 114-[5-(5-Acetyl-2-propoxyphenyl)-3-ethyl-7-oxo-6,7-dihydro-1H-pyrazolo[4,3-d]pyrimidin-1-yl]butanoicAcid

[0316]

[0317] 1N Sodium hydroxide solution (1 ml, 1 mmol) was added to asolution of the ester from example 9 (30 mg, 0.07 mmol) in dioxan (1 ml)and the reaction was stirred at room temperature for 2.5 hours. Thereaction was adjusted to pH 2 with 2N hydrochloric acid, stirred for 30min and the resulting precipitate was filtered and washed with water.The product was dried in vacuo to afford the title compound as a whitesolid, 13 mg.

[0318]¹H NMR (CDCl₃, 400 MHz) δ: 1.18 (t, 3H), 1.43 (t, 3H), 2.04 (m,2H), 2.30 (m, 2H), 2.41 (m, 2H), 2.68 (s, 3H), 3.02 (q, 2H), 4.27 (t,2H), 4.72 (t, 2H), 7.13 (d, 1H), 8.12 (d, 1H), 9.02 (s, 1H), 11.06 (brs,1H).

[0319] LRMS: m/z (ESP⁺) 427 [MH⁺], 449 [MNa⁺], 425 [MH⁻].

[0320] Microanalysis found: C, 61.45; H, 6.16; N, 12.92. C₂₂H₂₆N₄O₅. 0.2mol H₂O requires C, 61.44; H, 6.19; N, 13.03%.

Example 12

[0321]4-[5-(5-Acetyl-2-propoxyphenyl)-3-ethyl-7-oxo-6,7-dihydro-2H-pyrazolo[4,3-d]pyrimidin-2-yl]butanoicAcid

[0322] 1N Sodium hydroxide solution (1 ml, 1 mmol) was added to asolution of the ester from example 10 (25 mg, 0.06 mmol) in dioxan (1ml) and the reaction was stirred at room temperature for 3 hours. Thereaction was adjusted to pH 2 with 2N hydrochloric acid, diluted withwater (5 ml) and half of the solvent was removed under reduced pressure.The resulting precipitate was filtered, washed with water, dried invacuo and slurried with acetonitrile. The slurry was then filtered andthe solid was dried in vacuo to afford the title compound as a whitesolid, 13 mg.

[0323]¹H NMR (CDCl₃, 300 MHz) δ: 1.15 (t, 3H), 1.45 (t, 3H), 2.01 (m,2H), 2.35 (m, 2H), 2.49 (m, 2H), 2.67 (s, 3H), 3.09 (q, 2H), 4.26 (t,2H), 4.42 (t, 2H), 7.13 (d, 1H), 8.11 (d, 1H), 8.95 (s, 1H), 10.73 (brs, 1H).

[0324] LRMS: m/z (ESP⁺) 427 [MH⁺], 449 [MNa⁺]

[0325] Microanalysis found: C, 61.41; H, 6.12; N, 12.85. C₂₂H₂₆N₄O₅. 0.2mol H₂O requires C, 61.44; H, 6.19; N, 13.03%.

Example 132-[5-(5-Acetyl-2-propoxyphenyl)-3-ethyl-7-oxo-6,7-dihydro-2H-pyrazolo[4,3-d]pyrimidin-2-yl]-N,N-dimethylacetamide

[0326]

[0327] 2-Chloro-N,N-dimethylacetamide (178 mg, 1.47 mmol) was added to asuspension of cesium carbonate (480 mg, 1.47 mmol) and the pyrazole frompreparation 17 (500 mg, 1.47 mmol) in N,N-dimethylformamide (10 ml) atroom temperature, and the reaction was stirred for 84 hours. The mixturewas quenched with water and stood at room temperature for 18 hours, andthe resultant white solid was isolated by filtration and washed withwater, before being dried in vacuo. The solid was purified by columnchromatography on silica gel using dichloromethane:methanol:0.88 ammonia(95:5:0.5) to give two products, the most polar of which was collectedand crystallised from acetonitrile to afford the title compound as awhite solid, 132 mg.

[0328]¹H NMR (CDCl₃, 400 MHz) δ: 1.15 (t, 3H), 1.47 (t, 3H), 2.00 (m,2H), 2.64 (s, 3H), 3.05 (m, 5H), 3.18 (s, 3H), 4.23 (m, 2H), 5.20 (s,2H), 7.11 (d, 1H), 8.10 (d, 1H), 8.98 (s, 1H), 11.04 (br s, 1H).

[0329] LRMS: m/z (ESP⁺) 426 [MH⁺], 448 [MNa⁺].

[0330] Microanalysis found: C, 61.95; H, 6.38; N, 16.55. C₂₂H₂₇N₅O₄requires C, 61.95; H, 6.40; N, 16.46%.

Example 145-(5-Acetyl-2-propoxyphenyl)-3-propyl-2-(2-pyridinylmethyl)-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one

[0331]

[0332] Polyphosphoric acid (20 g) and the pyrazole carboxamide frompreparation 18 (1.3 g, 2.8 mmol) were heated to 190-200° C. for 15 minand the reaction was cooled to room temperature. The mixture wasquenched with water, basified to pH 8 with sodium carbonate andextracted with dichloromethane (×2). The combined organic extracts weredried over Na₂SO₄, concentrated under reduced pressure and the residuewas purified by column chromatography on silica gel usingdichloromethane:methanol (100:0 changing to 99:1 then 94:6) to affordthe title compound as an off-white solid, 30 mg. ¹H NMR (CDCl₃, 400 MHz)δ: 0.98 (t, 3H), 1.16 (t, 3H), 1.78 (m, 2H), 2.03 (m, 2H), 2.63 (s, 3H),3.00 (t, 2H), 4.25 (t, 2H), 5.69 (s, 2H), 7.09 (m, 2H), 7.22 (m, 1H),7.62 (t, I H), 8.09 (d, 1H), 8.58 (d, 1H), 8.99 (s, 1H), 10.62 (br s,1H).

[0333] LRMS: m/z (TSP⁺) 446.2 [MH⁺].

[0334] Preparation 1

[0335] 4-(2-n-Propoxybenzamido)-3-n-propyl-1H-pyrazole-5-carboxamide

[0336] A solution of 2-n-propoxybenzoyl chloride (57.6 g, 0.291 mol) indichloromethane (50 ml) was added dropwise to a stirred, ice-cooledsuspension of 4-amino-3-propyl-1H-pyrazole-5-carboxamide (the compoundof Preparation 8 of WO 98/49166) (35.0 g, 0.208 mol) in dry pyridine(350 ml) and the resulting mixture stirred for 18 hours at roomtemperature, then evaporated under reduced pressure. The residue wasazeotroped with toluene (2×100 ml) and the resulting brown solidtriturated with ether (100 ml) to give the title compound (83.0 g) as abeige solid.

[0337] δ (CH₃₀Hd₄): 0.92 (3H,t), 1.14 (3H,t), 1.65 (2H,m), 1.94 (2H,m),2.80 (2H,t), 4.20 (2H,t), 7.08 (1H,m), 7.18 (1H,d), 7.52 (1H,m), 8.04(1H,d). LRMS: m/z 331 (M+1)⁺.

[0338] Preparation 2

[0339]5-(2-n-Propoxyphenyl)-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one

[0340] Potassium t-butoxide (93.0 g, 0.832 mol) was added portionwise toa stirred solution of the title compound of Preparation 1 (83.0 g, 0.25mol) in propan-2-ol (800 ml) under nitrogen and the mixture heated for18 hours under reflux, then allowed to cool. Water (100 ml) was added,to produce a homogeneous solution which was acidified to pH 6 with 2Mhydrochloric acid. The resulting white precipitate was collected anddried by suction to provide the title compound (37.4 g). Found: C,65.36; H, 6.49; N, 17.99. C₁₇H₂₀N₄O₂ requires C, 65.37; H, 6.45; N,17.94%. 6 (CDCl₃): 1.05 (3H,t), 1.16 (3H,t), 2.00 (4H,m), 3.04 (2H,t),4.20 (2H,t), 7.07 (1H,d), 7.16 (1H,m), 7.48 (1H,m), 8.52 (1H,d), 11.30(1H,s), 12.25 (1H,s). LRMS: m/z 313 (M+1)⁺.

[0341] Preparation 3

[0342] 2-Cyanomethyl-5-(2-n-propoxyphenyl)-3-n-propyl-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one

[0343] A 2M solution of sodium bis(trimethylsilyl)amide intetrahydrofuran (4.42 ml, 8.8 mmol) was added to a stirred, ice-cooledsolution of the title compound of Preparation 2 (2.3 g, 7.4 mmol) intetrahydrofuran (25 ml) and the resulting solution stirred for 30minutes, before being cooled to about −70° C. Bromoacetonitrile (0.54ml, 7.7 mmol) was added dropwise, the cooling bath removed and, after afurther 20 hours, the reaction mixture carefully quenched with methanol(5 ml) and evaporated under reduced pressure. The residue was purifiedby column chromatography on silica gel, using an elution gradient ofdichloromethane:methanol (99:1 to 95:5), followed by crystallisationfrom hexane:ethyl acetate, to afford the title compound (1.89 g) as awhite solid. Found: C, 64.84; H, 5.98; N, 19.71. C₁₉H₂₁N₅O₂ requires C,64.94; H, 6.02; N, 19.93%. 8 (CDCl₃): 1.12 (6H,m), 1.98 (4H,m), 3.08(2H,t), 4.20 (2H,t), 5.26 (2H,s), 7.05 (1H,d), 7.16 (1H,m), 7.48 (1H,m),8.42 (1H,d), 11.00 (1H,s). LRMS: m/z 703 (2M+1)⁺.

[0344] Haloketones of the structure illustrated may be prepared viaFriedel-Crafts chemistry on intermediates such as the title compound ofPreparation 3 such as in known in the art.

[0345] Reaction of this halo ketone with an amine provides compoundshaving R⁴ functionality as detailed hereinbefore.

[0346] Preparation 4

[0347] Methyl 5-acetyl-2-butoxybenzoate

[0348] n-Butyl iodide (13.2 ml, 117 mmol) was added to a mixture ofmethyl 5-acetylsalicylate (15 g, 77 mmol) and potassium carbonate (16 g,117 mmol) in acetonitrile (500 ml), and the reaction stirred at 60° C.for 18 hours. TLC analysis showed starting material remaining, soadditional n-butyl iodide (26.4 ml, 234 mmol) and potassium carbonate(16 g, 117 mmol) were added and the reaction stirred at 60° C. for afurther 72 hours. The cooled mixture was concentrated under reducedpressure and the residue partitioned between ethyl acetate and water.The phases were separated, the organic layer washed with brine, dried(MgSO₄) and evaporated under reduced pressure to afford the titlecompound as a yellow oil that crystallised on drying in vacuo, 17.4 g.

[0349]¹H NMR (CDCl₃, 400 MHz) □: 0.99 (t, 3H), 1.54 (m, 2H), 1.82 (m,2H), 2.58 (s, 3H), 3.90 (s, 3H), 4.11 (t, 2H), 7.00 (d, 1H), 8.06 (dd,1H), 8.38 (d, 1H).

[0350] LRMS: m/z (TSP⁺) 251.1 [MH⁺]

[0351] Preparation 5

[0352] Methyl 5-acetyl-2-isobutoxybenzoate

[0353] 1-Iodo-2-methylpropane (13.35 ml, 117 mmol) was added to amixture of methyl 5-acetylsalicylate (15 g, 77 mmol) and potassiumcarbonate (16 g, 117 mmol) in acetonitrile (500 ml), and the reactionstirred at 60° C. for 18 hours. TLC analysis showed starting materialremaining, so additional 1-iodo-2-methylpropane (26.7 ml, 234 mmol) andpotassium carbonate (16 g, 117 mmol) were added and the reaction stirredat 60° C. for a further 72 hours. TLC analysis showed starting materialstill remaining, so additional 1-iodo-2-methylpropane (13.35 ml, 117mmol) and potassium carbonate (16 g, 117 mmol) were added and thereaction stirred at reflux for a further 3 hours. The cooled mixture wasconcentrated under reduced pressure and the residue partitioned betweenethyl acetate and 1N sodium hydroxide solution. The phases wereseparated, the aqueous extracted with further ethyl acetate, and thecombined organic solutions washed with brine, dried (MgSO₄) andevaporated under reduced pressure to give the title compound as a brownoil, 8.3 g.

[0354]¹H NMR (CDCl₃, 400 MHz) δ: 1.05 (d, 6H), 2.16 (m, 1H), 2.58 (s,3H), 3.85 (d, 2H), 3.90 (s, 3H), 6.99 (d,1H), 8.08 (dd, 1H), 8.39(d,1H).

[0355] LRMS: m/z (TSP⁺) 251.2 [MH⁺]

[0356] Preparation 6

[0357] 5-Acetyl-2-butoxybenzoic Acid

[0358] Sodium hydroxide pellets (5.6 g, 139 mmol) were added to asolution of the ester from preparation 4 (17.4 g, 70 mmol) in dioxan(400 ml) and water (40 ml), and the reaction stirred at room temperaturefor 18 hours. The mixture was concentrated under reduced pressure, theresidue acidifed to pH 1 using 2N hydrochloric acid, and the aqueousextracted with dichloromethane (250 ml, 3×100 ml). The combined organicsolutions were washed with brine, dried (MgSO₄) and evaporated underreduced pressure to give the title compound as an orange solid, 15.16 g.

[0359]¹H NMR (CDCl₃, 400 MHz) □: 1.02 (t, 3H), 1.57 (m, 2H), 1.96 (m,2H), 2.60 (s, 3H), 4.35 (t, 2H), 7.12 (d, 1H), 8.20 (d, 1H), 8.74 (s,1H).

[0360] LRMS: m/z (TSP⁺) 237.1 [MH⁺]

[0361] Preparation 7

[0362] 5-Acetyl-2-isobutoxybenzoic Acid

[0363] The title compound was obtained in 83% yield from the ester frompreparation 5, following the procedure described in preparation 6.

[0364]¹H NMR (CDCl₃, 400 MHz) □: 1.14 (d, 6H), 2.25 (m, 1H), 2.61 (s,3H), 4.10 (d, 2H), 7.13 (d, 1H), 8.20 (d, 1H), 8.77 (s, 1H).

[0365] LRMS: m/z (TSP⁺) 254.2 [MNH₄ ⁺]

[0366] Preparation 8

[0367]4-[(5-Acetyl-2-butoxybenzoyl)amino]-5-ethyl-1H-pyrazole-3-carboxamide

[0368] Oxalyl chloride (16.8 ml, 193 mmol) was added to an ice-cooledsolution of the acid from preparation 6 (15.16 g, 64 mmol) inN,N-dimethylformamide (0.5 ml) and dichloromethane (300 ml). Onceaddition was complete, the solution was allowed to warm to roomtemperature, and stirred for 1.5 hours. The solution was concentratedunder reduced pressure and azeotroped with dichloromethane (2×), thendried in vacuo. This intermediate acid chloride was dissolved indichloromethane (100 ml), triethylamine (27 ml, 193 mmol) added,followed by a solution of 4-amino-3-ethyl-1H-pyrazole-5-carboxamide (WO9849166) (9.9 g, 64 mmol) in dichloromethane (200 ml), and the reactionstirred at room temperature for 3 hours. The mixture was washed withsodium bicarbonate solution, this aqueous solution re-extracted withdichloromethane (4×100 ml), and the combined organic extracts dried(MgSO₄) and evaporated under reduced pressure. The residual brown solidwas triturated with ethyl acetate, the solid filtered, washed withdiethyl ether and dried. This solid was further purified by columnchromatography on silica gel using dichloromethane:methanol:0.88 ammonia(95:5:0.5) to afford the title compound as a beige solid, 20.12 g.

[0369]¹H NMR (CDCl₃, 400 MHz) □: 0.98 (t, 3H), 1.28 (t, 3H), 1.50 (m,2H), 1.98 (m, 2H), 2.60 (s, 3H), 2.97 (q, 2H), 4.35 (t, 2H), 5.38 (br s,1H), 6.78 (br s, 1H), 7.08 (d, 1H), 8.15 (dd, 1H), 8.81 (d, 1H), 10.38(br s, 1H).

[0370] LRMS: m/z (TSP⁺) 373.0 [MH⁺]

[0371] Microanalysis found: C, 60.85; H, 6.58; N, 14.73. C₁₉H₂₄N₄O₄requires C, 61.28; H, 6.50; N, 15.04%.

[0372] Preparation 9

[0373]4-[(5-Acetyl-2-isobutoxybenzoyl)amino]-5-ethyl-1H-pyrazole-3-carboxamide

[0374] The title compound was obtained as a beige solid in 86% yieldfrom the acid from preparation 7 and4-amino-3-ethyl-1H-pyrazole-5-carboxamide (WO 9849166), following asimilar procedure to that described in preparation 8. ¹H NMR (CDCl₃, 400MHz)]: 1.02 (d, 6H), 1.25 (t, 3H), 2.38 (m, 1H), 2.60 (s, 3H), 2.96 (q,2H), 4.06 (d, 2H), 5.33 (br s, 1H), 6.78 (br s, 1H), 7.08 (d, 1H), 8.15(d, 1H), 8.80 (s, 1H), 10.22 (s, 1H).

[0375] LRMS: m/z (ES+) 395 [MNa⁺]

[0376] Preparation 10

[0377] tert-Butyl3-[4-[(5-acetyl-2-butoxybenzovl)amino]-3-(aminocarbonyl)-5-ethyl-1H-pyrazol-1-yl]-1-azetidinecarboxylate

[0378] Cesium carbonate (19.7 g, 60.0 mmol) was added to a mixture ofthe pyrazole carboxamide from preparation 8 (15 g, 40 mmol) andtert-butyl-3-iodo-1-azetidinecarboxylate (EP 992493) (17.4 g, 60.0 mmol)in N,N-dimethylformamide (200 ml) and the reaction stirred at 50° C. for16 hours. TLC analysis showed starting material remaining, so additionaltert-butyl-3-iodo-1-azetidinecarboxylate (EP 992493) (6.0 g, 18.4 mmol)was added and the reaction stirred for a further 18 hours. The mixturewas concentrated under reduced pressure and the residue partitionedbetween ethyl acetate and sodium bicarbonate solution. The resultingsolid was filtered off, washed with ether and dried to give the titlecompound as a white solid, 6.8 g.

[0379] The filtrate was separated, the organic layer washed with brine,dried (MgSO₄) and evaporated under reduced pressure to give a brownsolid. This was triturated with ethyl acetate and warm diethyl ether,filtered and dried in vacuo, to afford additional product as a whitesolid, 8.2 g, (15.0 g in total).

[0380]¹H NMR (DMSOd₆, 400 MHz) l: 0.88 (t, 3H), 1.06 (t, 3H), 1.40 (m,11H), 1.82 (m, 2H), 2.54 (s, 3H), 2.70 (m, 2H), 4.26 (m, 6H), 5.32 (m, IH), 7.32 (m, 2H), 7.50 (br s, 1H), 8.08 (d, 1H), 8.42 (s, 1H), 10.00 (s,1H).

[0381] LRMS: m/z (TSP⁺) 528.1 [MH⁺]

[0382] Preparation 11

[0383] tert-Butyl3-[4-[(5-acetyl-2-isobutoxybenzoyl)amino]-3-(aminocarbonyl)-5-ethyl-1H-pyrazol-1-yl]-1-azetidinecarboxylate

[0384] Cesium carbonate (11.4 g, 35 mmol) was aded to a mixture of thepyrazole from preparation 9 (8.7 g, 23 mmol) andtert-butyl-3-iodo-1-azetidinecarboxylate (EP 992493) (19.9 g, 35 mmol)in N,N-dimethylformamide (100 ml) and the reaction stirred at 50° C. for16 hours. The cooled mixture was concentrated under reduced pressure andthe residue partitioned between water (250 ml)/saturated sodiumbicarbonate solution (200 ml) and ethyl acetate (100 ml). The layerswere separated, and the aqueous solution extracted with ethyl acetate(4×100 ml). The combined organic layers were washed with brine, dried(MgSO₄) and evaporated under reduced pressure to give a brown solid.This was purified by column chromatography on silica gel using anelution gradient of dichloromethane:methanol:0.88 ammonia (100:0:0 to97.5:2.5:0.25) to afford the title compound as a white solid, aftertrituration from ethyl acetate, 6.33 g.

[0385]¹H NMR (CDCl₃, 400 MHz) □: 1.02 (d, 6H), 1.18 (t, 3H), 1.46 (s,9H), 2.38 (m, 1H), 2.60 (s, 3H), 2.85 (q, 2H), 4.05 (d, 2H), 4.37 (m,2H), 4.44 (m, 2H), 5.08 (m, 1H), 5.28 (br s, 1H), 6.74 (br s, 1H), 7.06(d, 1H), 8.14 (dd, 1H), 8.78 (d, 1H), 10.17 (s, 1H).

[0386] LRMS: m/z (TSP⁺) 528.2 [MH⁺]

[0387] Preparation 12

[0388] tert-Butyl3-[5-(5-acetyl-2-butoxyphenyl)-3-ethyl-7-oxo-6,7-dihydro-2H-pyrazolo[4,3-d]pyrimidin-2-yl]-1-azetidinecarboxylate

[0389] Cesium carbonate (26.8 g, 83 mmol) was added to a mixture of thecompound from preparation 10 (14.5 g, 28 mmol), molecular sieves, andn-butyl acetate (3.6 ml, 28 mmol) in n-butanol (150 ml) and the reactionstirred at 140° C. for 10 hours. The cooled mixture was concentratedunder reduced pressure, the brown residue partitioned between ethylacetate and sodium bicarbonate solution, (some sonication required),then filtered. The filtrate was separated, the aqueous layer furtherextracted with ethyl acetate (4x), and the combined organic solutionswashed with brine, dried (MgSO₄) and evaporated under reduced pressure,to give the title compound, 8.3 g. ¹H NMR (CDCl₃, 400 MHz) □: 1.02 (t,3H), 1.38 (t, 3H), 1.46 (s, 9H), 1.58 (m, 2H), 1.98 (m, 2H), 2.62 (s,3H), 3.03 (q, 2H), 4.30 (m, 2H), 4.39 (m, 2H), 4.65 (bm, 2H), 5.23 (m,1H), 7.11 (d, 1H), 8.06 (dd, 1H), 8.98 (d, 1H), 10.60 (s, 1H).

[0390] Preparation 13

[0391] tert-Butyl3-[5-(5-acetyl-2-iso-butoxyphenyl)-3-ethyl-7-oxo-6,7-dihydro-2H-pyrazolo[4,3-d]pyrimidin-2-yl]-1-azetidinecarboxylate

[0392] The title compound was obtained in 90% yield as an orange foam,from the compound from preparation 11, iso-butanol and iso-butylacetate, following a similar procedure to that described in preparation12.

[0393]¹H NMR (CDCl₃, 400 MHz) □: 1.08 (d, 6H), 1.37 (t, 3H), 1.42 (s,9H), 2.25 (m, 1H), 2.60 (s, 3H), 3.00 (q, 2H), 4.00 (d, 2H), 4.37 (m,2H), 4.63 (bm, 2H), 5.22 (m, 1H), 7.05 (d, 1H), 8.03 (dd, 1H), 8.90 (d,1H), 10.52 (s, 1H).

[0394] LRMS m/z (TSP⁺) 410.1 [M-Boc]⁺

[0395] Preparation 14

[0396]5-(5-Acetyl-2-butoxyphenyl)-2-(3-azetidinyl)-3-ethyl-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-onetrifluoroacetate

[0397] Trifluoroacetic acid (4.3 ml) was added to a solution of theprotected azetidine from preparation 12 (2.84 g, 5.58 mmol) indichloromethane (15 ml), and the reaction stirred at room temperaturefor 1.5 hours. The solution was evaporated under reduced pressure, andthe residual brown gum triturated from dichloromethane (20 ml) anddiethyl ether (150 ml). The resulting solid was filtered, washed withfurther diethyl ether and dried in vacuo, to afford the title compoundas a beige solid, 3.06 g.

[0398]¹H NMR (CD₃OD, 400 MHz) □: 0.97 (t, 3H), 1.32 (t, 3H), 1.50 (m,2H), 1.82 (m, 2H), 2.60 (s, 3H), 3.03 (q, 2H), 4.22 (t, 2H), 4.65 (m,4H), 5.72 (m, 1H), 7.25 (d, 1H), 8.18 (d, 1H), 8.41 (s, I H).

[0399] LRMS :m/z (TSP⁺) 410.1 [MH⁺]

[0400] Preparation 15

[0401]5-(5-Acetyl-2-isobutoxyphenyl)-2-(3-azetidinyl)-3-ethyl-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-onetrifluoroacetate

[0402] The title compound was obtained as a beige solid, from theprotected azetidine from preparation 13, following a similar procedureto that described in preparation 14.

[0403]¹H NMR (CD₃OD, 400 MHz) □: 1.01 (d, 6H), 1.30 (t, 3H), 2.1.0 (m,1H), 2.60 (s, 3H), 3.05 (q, 2H), 4.00 (d, 2H), 4.65 (m, 4H), 5.72 (m,1H), 7.25 (d, 1H), 8.18 (dd, 1H), 8.38 (d, 1H).

[0404] LRMS: m/z (TSP⁺) 410.1 [MH⁺]

[0405] Preparation 16

[0406]4-[(5-Acetyl-2-propoxybenzoyl)amino]-5-ethyl-1H-pyrazole-3-carboxamide

[0407] Oxalyl chloride (5.45 ml, 46.4 mmol) was added to a solution of5-acetyl-2-n-propoxy-benzoic acid (WO 9312095) (11.1 g, 30.9 mmol) inN,N-dimethylformamide (0.1 ml) and dichloromethane (200 ml) undernitrogen at room temperature. Once addition was complete the solutionwas stirred for 1 hour. The solution was concentrated under reducedpressure and azeotroped with toluene, and the intermediate acid chloridewas dissolved in dichloromethane (200 ml). Triethylamine (10.4 ml, 46.4mmol) was added followed by 4-amino-3-ethyl-1H-pyrazole-5-carboxamide(WO 9849166) (7.7 g, 30.9 mmol) and the reaction was stirred at roomtemperature for 16 hours. The mixture was washed with 1N hydrochloricacid (2×100 ml), 10% sodium bicarbonate solution (100 ml) and brine (100ml), dried over Na₂SO₄ and the solvent was removed under reducedpressure. The residue was recrystallised from acetonitrile to afford thetitle compound as a crystalline solid, 14.8 g.

[0408]¹H NMR (CDCl₃, 400 MHz) □: 1.06 (t, 3H), 1.27 (t, 3H), 2.03 (m,2H), 2.62 (s, 3H), 2.95 (m, 2H), 4.29 (t, 2H), 5.43 (br s, 1H), 6.82 (brs, 1H), 7.10 (d, 1H), 8.16 (d, 1H), 8.84 (s, 1H), 10.39 (br s, 2H).

[0409] LRMS m/z (TSP⁺) 359.1 [MH⁺].

[0410] Microanalysis found: C, 60.04; H, 6.18; N, 15.79. C₁₈H₂₂N₄O₄requires C, 60.27; H, 6.18; N, 15.62%.

[0411] Preparation 17

[0412]5-[(5-Acetyl-2-propoxyphenyl)-3-ethyl-1,6-dihydro-pyrazolo[4,3-d]pyrimidin-7-one

[0413] Potassium tert-butoxide (4.37 g, 39 mmol) was added to a solutionof the pyrazole carboxamide from preparation 16 (14 g, 39 mmol) inn-propanol (120 ml) and ethyl acetate (10 ml) and the reaction wasstirred at reflux for 24 hours. TLC analysis showed starting materialremaining, so additional potassium tert-butoxide (4.37 g, 39 mmol) wasadded and the reaction was stirred at reflux for a further 18 hours.

[0414] TLC analysis still showed starting material, so another additionof potassium tert-butoxide (4.37 g, 39 mmol) was made and the reactionwas refluxed for a further 70 hours. The solvent was removed underreduced pressure and the residue was partitioned between dichloromethaneand water. The organic layer was removed, washed with water (2×), brine,dried over Na₂SO₄ and concentrated under reduced pressure. The residuewas purified by column chromatography on silica gel usingdichloromethane:methanol:0.88 ammonia (95:5:0.5) and the product wasrecrystallised from acetonitrile to afford the title compound as a whitesolid, 4.94 g.

[0415]¹H NMR (CDCl₃, 400 MHz) □: 1.18 (t, 3H), 1.50 (t, 3H), 2.03 (m,2H), 2.67 (s, 3H), 3.11 (q, 2H), 4.28 (t, 2H), 7.15 (d, 1H), 8.14 (d,1H), 9.08 (s, 1H), 11.59 (br s, 1H), 11.93 (br s, 1H).

[0416] LRMS: m/z (TSP⁺) 341.3 [MH⁺].

[0417] Microanalysis found: C, 63.18; H, 5.93; N, 12.22. C₁₈H₂₀N₄O₅requires C, 63.51; H, 5.92; N, 16.46%.

[0418] Preparation 18

[0419] 4-[(5-Acetyl-2-propoxybenzoyl)amino]-5-propyl-1-(pyridin-2-ylmethyl)-1H-pyrazole -3-carboxamide

[0420] Oxalyl chloride (1.6 ml, 18 mmol) was added to an ice-cooledsolution of 5-acetyl -2-n-propoxybenzoic acid (WO 9312095) (2 g, 9 mmol)in N,N-dimethylformamide (0.2 ml) and dichloromethane (200 ml) undernitrogen. Once addition was complete the solution was allowed to warm toroom temperature for 3 hours and the solvent was removed under reducedpressure. The intermediate acid chloride was dissolved in pyridine (50ml) and 4-amino-5-propyl-1-(pyridin-2-ylmethyl)-1H-pyrazole-3-carboxamide (WO 9954333) (1.5 g, 5.8 mmol) and the reaction wasstirred at reflux for 3 hours, then at room temperature for 18 hours.The mixture was partitioned between dilute sodium carbonate solution anddichloromethane, and the organic layer was dried over Na₂SO₄ andconcentrated under reduced pressure. The residue was purified by columnchromatography on silica gel using dichloromethane:methanol (100:0changing to 98:2 then 92:8) to afford the title compound as a beigesolid, 1.5 g.

[0421]¹H NMR (CDCl₃, 400 MHz) □: 0.81 (t, 3H), 1.06 (t, 3H), 1.46 (m,2H), 2.03 (m, 2H), 2.61 (s, 3H), 2.87 (m, 2H), 4.29 (t, 2H), 5.36 (br s,1H), 5.47 (s, 2H), 6.70 (br s, 1H), 6.94 (d, 1H), 7.09 (d, 1H), 7.22 (m,1H), 7.28 (m, 1H), 8.15 (d, 1H), 8.60 (m, 1H), 8.81 (s, 1H), 10.31 (brs,1H).

[0422] LRMS: m/z (TSP⁺) 464.3 [MH⁺].

1. A compound of general formula I:

or pharmaceutically or veterinarily acceptable salts, solvates,polymorphs or pro-drugs thereof wherein: A represents C(O) or CH(OH); Xrepresents 0 or NR⁵; R¹, R³, R⁴ and R⁵ independently represent H, C₁-C₆alkyl, Het, C₁-C₆ alkylHet, aryl or C₁-C₆ alkylaryl (which latter fivegroups may all be optionally substituted and/or terminated with one ormore substituents selected from halo, cyano, nitro, OR⁶, OC(O)R⁶,C(O)R⁶, C(O)OR⁶, NR⁶C(O)NR ⁷R⁸ NR⁶C(O)OR⁶, OC(O)NR⁷R⁸, C(O)NR⁹R¹⁰,NR⁹R¹⁰, SO₂NR⁹R¹⁰, SO₂R¹¹, C₁-C₆ alkyl, Het, C₁-C₆ alkylHet, aryl orC₁-C₆ alkylaryl wherein said latter five substituent and/or terminalgroups are all optionally substituted and/or terminated with one or moresubstituents selected from halo, cyano, nitro, OR¹², OC(O)R¹², C(O)R¹²,C(O)OR¹², NR¹²(O)NR¹³R¹⁴, NR¹²C(O)OR¹², OC(O)NR¹³R¹⁴, C(O)NR¹⁵R¹⁶,NR¹⁵R¹⁶, SO₂NR¹⁵R¹⁶, S₂R¹⁷); or when X represents NR⁵ then R and R⁵together with the nitrogen atom to which they are bound can form aheterocyclic ring which is optionally substituted and/or terminated withone or more substituents selected from halo, cyano, nitro, OR¹²,OC(O)R¹², C(O)R¹², C(O)OR¹², NR¹²C(O)NR¹³R¹⁴, NR¹²C(O)OR¹²,OC(O)NR¹³R¹⁴, C(O)NR¹⁵R¹⁶, NR¹⁵R¹⁶, SO₂NR¹⁵R¹⁶, SO₂R¹⁷; R² represents H,halo, cyano, nitro, OR⁶, OC(O)R⁶, C(O)R⁶, C(O)OR⁶, NR⁶C(O)NR⁷R⁸,NR⁶C(O)OR⁶, OC(O)NR⁷R⁸, C(O)NR⁹R¹⁰, NR⁹R¹⁰, SO₂NR⁹R¹⁰, SO₂R¹¹, C₁-C₆alkyl, Het, C₁-C₆ alkylHet, aryl or C₁-C₆ alkylaryl (which latter fivegroups may all be optionally substituted and/or terminated with one ormore substituents selected from halo, cyano, nitro, OR⁶, OC(O)R⁶,C(O)R⁶, C(O)OR⁶, NR⁶C(O)NR⁷R⁸, NR⁶C(O)OR⁶, OC(O)NR⁷R⁸, C(O)NR⁹R¹⁰,NR⁹R¹⁰, SO₂NR⁹R¹⁰, SO₂R¹¹, C₁-C₆ alkyl, Het, C₁-C₆ alkylHet, aryl orC₁-C₆ alkylaryl wherein said latter five substituent and/or terminalgroups are all optionally substituted and/or terminated with one or moresubstituents selected from halo, cyano, nitro, OR¹², OC(O)R¹², C(O)R¹²C(O)OR¹² NR¹²C(O)NR¹³R¹⁴, NR¹²(O)OR¹², OC(O)NR R , C(O)NR¹³R¹⁴, NR¹⁵R¹⁶,SO₂NR¹⁵R¹⁶ SO₂R¹⁷); R⁶ represents H, C₁-C₆ alkyl, Het, C₁-C₆ alkylHet,aryl or C₁-C₆ alkylaryl (which latter five groups are all optionallysubstituted and/or terminated with one or more substituents selectedfrom halo, cyano, nitro, OR¹², OC(O)R¹², C(O)R¹², C(O)OR¹²,NR¹²C(O)NR¹³R¹⁴, NR¹²C(O)OR¹², OC(O)NR¹³R¹⁴, C(O)NR¹⁵R¹⁶, NR R⁶,SO₂NR¹⁵R¹⁶, SO₂R¹⁷); R⁷ and R⁸ independently represent H, C₁-C₆ alkyl,Het, C₁-C₆ alkylHet, aryl or C₁-C₆ alkylaryl (which latter five groupsare all optionally substituted and/or terminated with one or moresubstituents selected from halo, cyano, nitro, OR¹², OC(O)R¹², C(O)R¹²,C(O)OR 12, NR C(O)NR¹³R¹⁴, NR¹²C(O)OR¹², OC(O)NR¹³R¹⁴, C(O)NR¹⁵R¹⁶,NR¹⁵R¹⁶, SO₂NR¹⁵R¹⁶, SO₂R¹⁷); or R⁷ and R⁸ together with the nitrogenatom to which they are bound can form a heterocyclic ring; R⁹ and R¹⁰independently represent H, C(O)R⁶, SO₂R¹¹, C₁-C₆ alkyl, Het, C₁-C₆alkylHet, aryl or C₁-C₆ alkylaryl (which latter five groups are alloptionally substituted and/or terminated with one or more substituentsselected from halo, cyano, nitro, OR¹², OC(O)R¹², C(O)R¹², C(O)OR¹²,NR¹²C(O)NR¹³R¹⁴, NR¹²C(O)OR¹², OC(O)NR¹³R¹⁴, C(O)NR¹⁵R¹⁶, NR¹⁵R¹⁶,SO₂NR¹⁵R¹⁶, SO₂R¹⁷); or R⁹ and R¹⁰ together with the nitrogen atom towhich they are bound can form a heterocyclic ring; wherein when R⁷ andR⁸, or R⁹ and R¹⁰ together with the nitrogen atom to which they arebound form a heterocyclic ring, said heterocyclic ring is optionallysubstituted and/or terminated with one or more substituents selectedfrom: halo, cyano, nitro, OR¹², OC(O)R¹², C(O)R¹², C(O)OR¹²,NR¹²C(O)NR¹³R¹⁴, NR¹²C(O)OR¹², C(O)NR¹³R¹⁴, C(O)NR¹⁵R¹⁶, NR¹⁵R¹⁶,SO₂NR¹⁵R¹⁶, SO₂R ; R¹¹ represents a C₁-C₆ alkyl, Het, C₁-C₆ alkylHet,aryl or C₁-C₆ alkylaryl group is optionally substituted and/orterminated with one or more substituents selected from halo, cyano,nitro, OR , OC(O)R¹², C(O)R¹², C(O)OR¹², NR¹²C(O)NR¹³R¹⁴, NR¹²C(O)OR¹²,OC(O)NR¹³R¹⁴, C(O)NR¹⁵R¹⁶, NR¹⁵R¹⁶, SO₂NR¹⁵R¹⁶, SO₂R¹⁷; R¹² represents Hor C₁-C₆ alkyl; R¹³ and R¹⁴ independently represent H or C₁-C₆ alkyl; orR¹³ and R¹⁴ together with the nitrogen atom to which they are bound canform a heterocyclic ring; R¹⁵ and R¹⁶ independently represent H,C(O)R¹², SO₂R¹⁷ or C₁-C₆ alkyl; or R¹⁵ and R¹⁶ together with thenitrogen atom to which they are bound can form a heterocyclic ring; R¹⁷represents C₁-C₆ alkyl; Het represents an optionally substituted four-to twelve-membered heterocyclic group, which group contains one or moreheteroatoms selected from nitrogen, oxygen, sulpur and mixtures thereof;with the proviso that when X represents O and R¹ represents H, C₁-C₃alkyl optionally substituted with fluoro or C₃-C₅ cycloalkyl then R²does not represent H, C₁-C₆ alkyl optionally substituted with one ormore fluoro substituents or with C₃-C₆ cycloalkyl; or R³ does notrepresent C₁-C₆ alkyl optionally substituted with one or morfluorosubstituents or with C₃-C₆ cycloalkyl; C₃-C₅ cycloalkyl; C₃-C₆ alkenyl;or C₃-C₆ alkynyl; or R⁴ does not represent C₁-C₄ alkyl optionallysubstituted with OH, NR⁹ R¹⁰, CN, CONR⁹R¹⁰, SO₂NR⁹R¹⁰ or CO₂R⁶ whereinR⁶ is H or C₁-C₄ alkyl and R⁹ and R¹⁰ are each independently H or C₁-C₄alkyl, or together with the nitrogen atom to which they are attachedform a pyrrolidinyl, piperidino, morpholino, 4-substituted piperizinylor imidazolyl group wherein said group is optionally substituted withC₁-C₄ alkyl or OH; C₂-C₄ alkenyl optionally substitued with CN, CONR⁹R¹⁰or CO₂R⁶; C₂-C₄ alkanoyl optionally substituted with NR⁹R¹⁰; (C₂-C₄)OHoptionally substitued with NR⁹R¹⁰; (C₂-C₃)alkoxy(C₁-C₂)alkyl optionallysubstituted with OH or NR⁹R¹⁰.
 2. A compound as defined in claim 1wherein: X represents O; A represents C(O) or CH(OH); R¹ representsC₁-C₆ alkyl substituted and/or terminated with OR⁶, C(O)OR⁶, C(O)NR⁹R¹⁰or NR⁹R¹⁰ wherein said latter four groups are optionally substitutedand/or terminated as defined hereinbefore; or R¹ represents Het, C₁-C₆alkylHet, aryl or C₁-C₆ alkylaryl optionally substituted and/orterminated with one or more substituents selected from halo, C₁-C₆alkyl, OR⁶, C(O)OR , C(O)NR⁹R¹⁰ and NR⁹R¹⁰ wherein said latter fivegroups are optionally substituted and/or terminated as definedhereinbefore; R² and R³ independently represent C₁-C₆ alkyl, Het, C₁-C₆alkylHet, aryl or C₁-C₆ alkylaryl optionally substituted and/orterminated with one or more substituents selected from halo, OR⁶,C(O)OR⁶ and NR⁹R¹⁰ wherein said latter three groups are optionallysubstituted and/or terminated as defined hereinbefore; R⁴ representsC₁-C₆ alkyl, Het, C₁-C₆ alkylHet, aryl or C₁-C₆ alkylaryl optionallysubstituted and/or terminated with one or more substituents selectedfrom halo and OR⁶ wherein said OR⁶ group is optionally substitutedand/or terminated as defined hereinbefore; wherein R⁶, R⁹ and R¹⁰ are ashereinbefore defined.
 3. A compound as defined in claim 1 or 2 wherein:A represents C(O) and X represents O; R¹ represents C₁-C₆ alkyloptionally substituted and/or terminated with one or more substituentgroups selected from OR⁶ ₇ C(O)OR⁶ and C(O)NR⁹R¹⁰; or R¹ represents Hetor C₁-C₆ alkylHet optionally substituted and/or terminated with one ormore substituent groups selected from C₁-C₆ alkyl, OR⁶, C(O)OR⁶ andC(O)NR⁹R¹⁰; R² represents C₁-C₆ alkyl optionally substituted and/orterminated with one or more substituent groups selected from halo andOR⁶; R³ represents C₁-C₆ alkyl optionally substituted and/or terminatedwith one or more substituents selected from halo and OR⁶; R⁴ representsC₁-C₆ alkyl optionally substituted and/or terminated with one or moresubstituents selected from halo and OR⁶; wherein R⁶, R⁹ and R¹⁰ are ashereinbefore defined.
 4. A compound as defined in any of the precedingclaims wherein: A represents C(O) and X represents O; R¹ representsC₁-C₄ alkyl, an azetidinyl group substituted and/or terminated with oneor more substituent groups selected from C₃-C₄ alkyl, OR⁶, C(O)OR⁶ andC(O)NR⁹R¹⁰; or R¹ represents a (C₁-C₆)pyridinyl group which may beoptionally substuted C(O)OR⁶ and C(O)NR⁹R¹⁰; R² represents C₁-C₃ alkyloptionally substituted and/or terminated with one or more substituentgroups selected from halo and OR⁶, R³ represents C₁-C₄ alkyl optionallysubstituted and/or terminated with one or more substituents selectedfrom halo and OR⁶; R⁴ represents C₁-C₃ alkyl optionally substitutedand/or terminated with one or more substituents selected from halo andOR⁶; wherein R⁶ is H or a C₁-C₄ alkyl group and wherein R⁹ and R¹⁰ areindependently selected from methyl or ethyl groups.
 5. A compoundaccording to any of the preceding claims wherein: A represents C(O) andX represents O; R¹ represents C₂-C₃ alkyl group substituted and/orterminated with one or more substituent groups selected from OR⁶ orC(O)OR⁶; R² represents C₂-C₃ alkyl, and is preferably ethyl, optionallysubstituted and/or terminated with one or more substituent groupsselected from halo and OR⁶; R³ represents C₃-C₄ alkyl, and is preferablypropyl, optionally substituted and/or terminated with one or moresubstituents selected from halo and OR⁶; R⁴ represents C₁-C₂ alkyl, andis preferably ethyl, optionally substituted and/or terminated with oneor more substituents selected from halo and OR⁶; wherein R⁶ is H or aC₂-C₄ alkyl group.
 6. Compound as defined in any of claims 1 to 5 foruse as a pharmaceutical or as an animal medicament.
 7. A formulationcomprising a compound as defined in any of claims 1 to 5 in admixturewith a pharmaceutically or veterinarily acceptable adjuvant, diluent orcarrier.
 8. The use of a compound as defined in any of claims 1 to 5 inthe manufacture of a medicament for the curative or prophylactictreatment of a medical condition for which inhibition of cGMP PDE5 isdesired.
 9. Use as claimed in claim 8 wherein the condition is maleerectile dysfunction (MED), impotence, female sexual dysfunction (FSD),clitoral dysfunction, female hypoactive sexual desire disorder, femalesexual arousal disorder, female sexual pain disorder or female sexualorgasmic dysfunction (FSOD) or a cardiovascular disorder.
 10. The use ofa compound of general formula I:

or pharmaceutically or veternarily acceptable saltsm slovates,polymorphs or pro-drugs thereof wherein: A represents C(O) or CH(OH); Xrepresents O or NR⁵; R¹, R³, R⁴ and R⁵ independently represent H, C₁-C₆alkyl, Het, C₁-C₆ alkylHet, aryl or C₁-C₆ alkylaryl (which latter fivegroups may all be optionally substituted and/or terminated with one ormore substituents selected from halo, cyano, nitro, OR⁶, OC(O)R⁶,C(O)R⁶, C(O)OR⁶, NR⁶C(O)NR⁷R⁸, NR⁶C(O)OR⁶, C(O)NR⁷R⁸, C(O)NR⁹R¹⁰,NR⁹R¹⁰, SO₂NR⁹R¹⁰, SO₂R¹¹, C₁-C₆, alkyl, Het, C₁-C₆ alkylHet, aryl orC₁-C₆ alkylaryl wherein said latter five substituent and/or terminalgroups are all optionally substituted and/or terminated with one or moresubstituents selected from halo, cyano, nitro, OR , OC(O)R¹², C(O)R¹²,C(O)OR¹², NR¹²C(O)NR¹³R¹⁴, NR¹²C(O)OR¹², OC(O)NR¹³R¹⁴, C(O)NR¹⁵R¹⁶,NR¹⁵R¹⁶, SO₂NR¹⁵R¹⁶, SO₂R¹⁷); or when X represents NR⁵ then R³ and R⁵together with the nitrogen atom to which they are bound can form aheterocyclic ring which is optionally substituted and/or terminated withone or more substituents selected from halo, cyano, nitro, OR¹²,OC(O)R¹², C(O)R¹², C(O)OR¹², NR¹²C(O)NR¹³R¹⁴, NR¹²C(O) R¹²,OC(O)NR¹³R¹⁴, C(O)NR¹⁵R¹⁶ NR¹⁵R¹⁶, SO₂NR¹⁵R¹⁶, SO₂R¹⁷; R² represents H,halo, cyano, nitro, OR⁶, OC(O)R⁶, C(O)R⁶, C(O)OR⁶, NR⁶C(O)NR⁷R, NRC(O)OR, OC(O)NR R C(O)NR⁹R¹⁰, NR⁹R¹⁰, SO₂NR⁹R¹⁰, SO₂R¹¹, C₁-C₆ alkyl,Het, C₁-C₆ alkylHet, aryl or C₁-C₆ alkylaryl (which latter five groupsmay all be optionally substituted and/or terminated with one or moresubstituents selected from halo, cyano, nitro, OR⁶, OC(O)R⁶, C(O)R⁶,C(O)OR⁶, NR⁶C(O)NR⁷R⁸, NR⁶C(O)OR⁶, OC(O)NR⁷R⁸, C(O)NR⁹R¹⁰, NR⁹R¹⁰,SO₂NR⁹R¹⁰, SO₂R¹¹, C₁-C₆ alkyl, Het, C₁-C₆ alkylHet, aryl or C₁-C₆alkylaryl wherein said latter five substituent and/or terminal groupsare all optionally substituted and/or terminated with one or moresubstituents selected from halo, cyano, nitro, OR¹², OC(O)R¹², C(O)R¹²,C(O)OR¹², NR¹²C(O)NR¹³R¹⁴, NR (O)OR², OC(O)NR¹³R¹⁴, C(O)NR¹⁵R¹⁶, NR¹⁵R¹⁶SO₂NR¹⁵R¹⁶, SO₂R¹⁷); R⁶ represents H, C₁-C₆ alkyl, Het, C₁-C₆ alkylHet,aryl or C₁-C₆ alkylaryl (which latter five groups are all optionallysubstituted and/or terminated with one or more substituents selectedfrom halo, cyano, nitro, OR¹², OC(O)R¹², C(O)R¹², C(O)OR¹²,NR¹²C(O)NR¹³R¹⁴, NR¹²C(O)OR¹², OC(O)NR¹³R¹⁴, C(O)NR¹⁵R¹⁶, NR¹⁵R¹⁶,SO₂NR¹⁵R¹⁶, SO₂R¹⁷); R⁷ and R⁸ independently represent H, C₁-C₆ alkyl,Het, C₁-C₆ alkylHet, aryl or C₁-C₆ alkylaryl (which latter five groupsare all optionally substituted and/or terminated with one or moresubstituents selected from halo, cyano, nitro, OR¹², OC(O)R¹², C(O)R¹²,C(O)OR¹² NR 12C(O)NR¹³R¹⁴, NR¹²C(O)OR¹², OC(O)NR¹³R¹⁴, C(O)NR¹⁵R¹⁶,NR¹⁵R¹⁶, SO₂NR¹⁵R¹⁶, SO₂R¹⁷); or R⁷ and R⁸ together with the nitrogenatom to which they are bound can form a heterocyclic ring; R⁹ and R¹⁰independently represent H, C(O)R⁶, SO₂R¹¹, C₁-C₆ alkyl, Het, C₁-C₆alkylHet, aryl or C₁-C₆ alkylaryl (which latter five groups are alloptionally substituted and/or terminated with one or more substituentsselected from halo, cyano, nitro, OR¹², OC(O)R¹², C(O)R¹², C(O)OR¹²,NR¹²C(O)NR¹³R¹⁴, NR¹²C(O)OR¹², C(O)NR¹³R¹⁴, C(O)NR¹⁵R¹⁶, NR¹⁵R¹⁶,SO₂NR¹⁵R¹⁶, SO₂R¹⁷); or R⁹ and R¹⁰ together with the nitrogen atom towhich they are bound can form a heterocyclic ring; wherein when R⁷ andR⁸, or R⁹ and R¹⁰ together with the nitrogen atom to which they arebound form a heterocyclic ring, said heterocyclic ring is optionallysubstituted and/or terminated with one or more substituents selectedfrom: halo, cyano, nitro, OR , OC(O)R¹², C(O)R¹², C(O)OR¹²,NR¹²C(O)NR¹³R¹⁴, NR¹²C(O)OR¹², OC(O)NR¹³R¹⁴, C(O)NR¹⁵R¹⁶, NR¹⁵R¹⁶,SO₂NR¹⁵R¹⁶, SO₂R¹⁷; R¹¹ represents a C₁-C₆ alkyl, Het, C₁-C₆ alkylHet,aryl or C₁-C₆ alkylaryl group is optionally substituted and/orterminated with one or more substituents selected from halo, cyano,nitro, OR¹², OC(O)R¹², C(O)R¹², C(O)OR¹², NR¹²C(O)NR¹³R¹⁴, NR¹²C(O)OR¹²,OC(O)NR¹³R¹⁴, C(O)NR¹⁵R¹⁶, NR¹⁵R¹⁶, SO₂NR¹⁵R¹⁶, SO₂R¹⁷; R¹² represents Hor C₁-C₆ alkyl; R¹³ and R¹⁴ independently represent H or C₁-C₆ alkyl; orR¹³ and R¹⁴ together with the nitrogen atom to which they are bound canform a heterocyclic ring; R¹⁵ and R¹⁶ independently represent H,C(O)R¹², SO₂R or C₁-C₆ alkyl; or R¹⁵ and R¹⁶ together with the nitrogenatom to which they are bound can form a heterocyclic ring; R¹⁷represents C₁-C₆ alkyl; Het represents an optionally substituted four-to twelve-membered heterocyclic group, which group contains one or moreheteroatoms selected from nitrogen, oxygen, sulpur and mixtures thereofin the manufacture of a medicament for the curative or prophylactictreatment of a medical condition selected from premature labour,dysmenorrhoea, nitrate induced tolerance, pre-eclampsia, Kawasaki'ssyndrome, nitrate tolerance, multiple sclerosis, diabetic nephropathy,neuropathy including autonomic and peripheral neuropathy and inparticular diabetic neuropathy and symptoms thereof (e.g.gastroparesis), peripheral diabetic neuropathy, Alzheimer's disease,acute respiratory failure, psoriasis, skin necrosis, cancer, metastasis,baldness, nutcracker oesophagus, anal fissure, haemorrhoids, hypoxicvasoconstriction, , hypoxic vasoconstriction, diabetes, type 2 diabetesmellitus, the insulin resistance syndrome, insulin resistance, impairedglucose tolerance, as well as the stabilisation of blood pressure duringhaemodialysis.